Sulfoximine substituted quinazolines for pharmaceutical compositions

ABSTRACT

This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R 1  and R 2  are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

FIELD OF THE INVENTION

This invention relates to sulfoximine substituted quinazolinederivatives and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a orMNK2b) kinase inhibitors, pharmaceutical compositions containing themand their use in the treatment or amelioration of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) mediated disorders.

Moreover, the present invention relates to the use of sulfoximinesubstituted quinazoline derivatives of the invention for the productionof pharmaceutical compositions for the prophylaxis and/or treatment ofdiseases which can be influenced by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) orfurther variants thereof. Particularly, the present invention relates tothe use of sulfoximine substituted quinazoline derivatives of theinvention for the production of pharmaceutical compositions for theprophylaxis and/or therapy of metabolic diseases, such as diabetes,hyperlipidemia and obesity, hematopoietic disorders, neurodegenerativediseases, kidney damage, inflammatory disorders, and cancer and theirconsecutive complications and disorders associated therewith.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

The present invention is more particularly directed to the treatmentand/or prophylaxis of in particular metabolic diseases of the lipid andcarbohydrate metabolism and the consecutive complications and disordersassociated therewith.

Lipid disorders cover a group of conditions which cause abnormalities inthe level and metabolism of plasma lipids and lipoproteins. Thus,hyperlipidemias are of particular clinical relevance since theyconstitute an important risk factor for the development ofatherosclerosis and subsequent vascular diseases such as coronary heartdisease.

Diabetes mellitus is defined as a chronic hyperglycemia associated withresulting damages to organs and dysfunctions of metabolic processes.Depending on its etiology, one differentiates between several forms ofdiabetes, which are either due to an absolute (lacking or decreasedinsulin secretion) or to a relative lack of insulin. Diabetes mellitusType I (IDDM, insulin-dependent diabetes mellitus) generally occurs inadolescents under 20 years of age. It is assumed to be of auto-immuneetiology, leading to an insulitis with the subsequent destruction of thebeta cells of the islets of Langerhans which are responsible for theinsulin synthesis. In addition, in latent autoimmune diabetes in adults(LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyeddue to autoimmune attack. The amount of insulin produced by theremaining pancreatic islet cells is too low, resulting in elevated bloodglucose levels (hyperglycemia). Diabetes mellitus Type II generallyoccurs at an older age. It is above all associated with a resistance toinsulin in the liver and the skeletal muscles, but also with a defect ofthe islets of Langerhans. High blood glucose levels (and also high bloodlipid levels) in turn lead to an impairment of beta cell function and toan increase in beta cell apoptosis.

Diabetes is a very disabling disease, because today's commonanti-diabetic drugs do not control blood sugar levels well enough tocompletely prevent the occurrence of high and low blood sugar levels.Out of range blood sugar levels are toxic and cause long-termcomplications for example retinopathy, renopathy, neuropathy andperipheral vascular disease. There is also a host of related conditions,such as obesity, hypertension, heart disease and hyperlipidemia, forwhich persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

In one embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of metabolic diseases of the carbohydrate metabolismand their consecutive complications and disorders such as impairedglucose tolerance, diabetes (preferably diabetes type II), diabeticcomplications such as diabetic gangrene, diabetic arthropathy, diabeticosteopenia, diabetic glomerosclerosis, diabetic nephropathy, diabeticdermopathy, diabetic neuropathy, diabetic cataract and diabeticretinopathy, diabetic maculopathy, diabetic feet syndrome, diabetic comawith or without ketoacidosis, diabetic hyperosmolar coma, hypoglycemiccoma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis,intracapillary glomerulonephrosis, Kimmelstiel-Wilson syndrome, diabeticamyotrophy, diabetic autonomic neuropathy, diabetic mononeuropathy,diabetic polyneuropathy, diabetic angiopathies, diabetic peripheralangiopathy, diabetic ulcer, diabetic arthropathy, or obesity indiabetes.

In a further embodiment the compounds and compositions of the presentinvention are useful for the treatment and/or prophylaxis of metabolicdiseases of the lipid metabolism (i.e. lipid disorders) and theirconsecutive complications and disorders such as hypercholesterolemia,familial hypercholesterolemia, Fredrickson's hyperlipoproteinemia,hyperbetalipoproteinemia, hyperlipidemia, low-density-lipoprotein-type[LDL] hyperlipoproteinemia, pure hyperglyceridemia, endogenoushyperglyceridemia, isolated hypercholesterolemia, isolatedhypertroglyceridemia, cardiovascular diseases such as hypertension,ischemia, varicose veins, retinal vein occlusion, atherosclerosis,angina pectoris, myocardial infarction, stenocardia, pulmonaryhypertension, congestive heart failure, glomerulopaty, tubulointestitialdisorders, renal failure, angiostenosis, or cerebrovascular disorders,such as cerebral apoplexy.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of hematopoetic disorders and their consecutivecomplications and disorders such as acute myeloid leukemia (AML), MorbusHodgkin, Non-Hodgkin's lymphoma; hematopoetic disease, acutenon-lymphocytic leukemia (ANLL), myeloproliferative disease acutepromyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL),multiple myeloma, polycythemia vera, lymphoma, acute lymphocyticleukemia (ALL), chronic lymphocytic leukemia (CCL), Wilm's tumor, orEwing's Sarcoma.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cancer and consecutive complications and disorderssuch as cancer of the upper gastrointestinal tract, pancreaticcarcinoma, breast cancer, colon cancer, ovarian carcinoma, cervixcarcinoma, endometrial cancer, brain tumor, testicular cancer, laryngealcarcinoma, osteocarcinoma, prostatic cancer, retinoblastoma, livercarcinoma, lung cancer, neuroblastoma, renal carcinoma, thyroidcarcinoma, esophageal cancer, soft tissue sarcoma, skin cancer,osteosarcoma, rhabdomyosarcoma, bladder cancer, metastatic cancer,cachexia, or pain.

Certain anti-cancer drugs such as cisplatin are linked to serious sideeffects such as nephrotoxicity or ototoxicity, which can be doselimiting. Activation of MNKs has been linked to these side effects. In afurther embodiment of the present invention, the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of ear or kidney damage, in particular for theprevention or treatment of ear and kidney drug induced damage.

Furthermore, the present invention relates to the use of the compoundsaccording to the invention for the production of pharmaceuticalcompositions for the prophylaxis and/or therapy of cytokine relateddiseases.

Such diseases are i.a. inflammatory diseases, autoimmune diseases,destructive bone disorders, proliferative disorders, infectiousdiseases, neurodegenerative diseases, allergies, or other conditionsassociated with proinflammatory cytokines.

Allergic and inflammatory diseases such as acute or chronicinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, asthma and septic shock andtheir consecutive complications and disorders associated therewith.

Inflammatory diseases like rheumatoid arthritis, inflammatory lungdiseases like COPD, inflammatory bowel disease and psoriasis afflict onein three people in the course of their lives. Not only do those diseasesimpose immense health care costs, but also they are often crippling anddebilitating.

Although inflammation is the unifying pathogenic process of theseinflammatory diseases below, the current treatment approach is complexand is generally specific for any one disease. Many of the currenttherapies available today only treat the symptoms of the disease and notthe underlying cause of inflammation.

The compositions of the present invention are useful for the treatmentand/or prophylaxis of inflammatory diseases and consecutivecomplications and disorders. such as chronic or acute inflammation,inflammation of the joints such as chronic inflammatory arthritis,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenilerheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis,rubella arthritis, acute synovitis and gouty arthritis; inflammatoryskin diseases such as sunburn, psoriasis, erythrodermic psoriasis,pustular psoriasis, eczema, dermatitis, acute or chronic graftformation, atopic dermatitis, contact dermatitis, urticaria andscleroderma; inflammation of the gastrointestinal tract such asinflammatory bowel disease, Crohn's disease and related conditions,ulcerative colitis, colitis, and diverticulitis; nephritis, urethritis,salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupuserythematosus and related disorders, multiple sclerosis, asthma,meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis,thrombophlebitis, respiratory diseases such as asthma, bronchitis,chronic obstructive pulmonary disease (COPD), inflammatory lung diseaseand adult respiratory distress syndrome, and allergic rhinitis;endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis,rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valvedisease, rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis.oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Moreover, cytokines are also believed to be implicated in the productionand development of various cardiovascular and cerebrovascular disorderssuch as congestive heart disease, myocardial infarction, the formationof atherosclerotic plaques, hypertension, platelet aggregation, angina,stroke, Alzheimer's disease, reperfusion injury, vascular injuryincluding restenosis and peripheral vascular disease, and, for example,various disorders of bone metabolism such as osteoporosis (includingsenile and postmenopausal osteoporosis), Paget's disease, bonemetastases, hypercalcaemia, hyperparathyroidism, osteosclerosis,osteoporosis and periodontitis, and the abnormal changes in bonemetabolism which may accompany rheumatoid arthritis and osteoarthritis.

Excessive cytokine production has also been implicated in mediatingcertain complications of bacterial, fungal and/or viral infections suchas endotoxic shock, septic shock and toxic shock syndrome and inmediating certain complications of CNS surgery or injury such asneurotrauma and ischaemic stroke.

Excessive cytokine production has, moreover, been implicated inmediating or exacerbating the development of diseases involvingcartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renalfibrosis, the cachexia found in certain chronic diseases such asmalignant disease and acquired immune deficiency syndrome (AIDS), tumourinvasiveness and tumour metastasis and multiple sclerosis. The treatmentand/or prophylaxis of these diseases are also contemplated by thepresent invention

Additionally, the inventive compositions may be used to treatinflammation associated with autoimmune diseases including, but notlimited to, systemic lupus erythematosis, Addison's disease, autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),glomerulonephritis, rheumatoid arthritis scleroderma, chronicthyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmunehemolytic anemia, glomerulonephritis, rheumatoid arthritis autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, and graft vs.host disease.

In a further embodiment the compositions of the present invention may beused for the treatment and prevention of infectious diseases such assepsis, septic shock, Shigellosis, and Helicobacter pylori and viraldiseases including herpes simplex type 1 (HSV-1), herpes simplex type 2(HSV-2), cytomegalovirus, Epstein-Barr, human immunodeficiency virus(HIV), acute hepatitis infection (including hepatitis A, hepatits B, andhepatitis C), HIV infection and CMV retinitis, AIDS or malignancy,malaria, mycobacterial infection and meningitis. These also includeviral infections, by influenza virus, varicella-zoster virus (VZV),Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7(HHV-7), human herpesvirus-8 (HHV-8), Poxvirus, Vacciniavirus,Monkeypoxvirus, pseudorabies and rhinotracheitis.

The compositions of the present invention may also be used topically inthe treatment or prophylaxis of topical disease states mediated by orexacerbated by excessive cytokine production, such as inflamed joints,eczema, psoriasis and other inflammatory skin conditions such assunburn; inflammatory eye conditions including conjunctivitis; pyresis,pain and other conditions associated with inflammation.

Periodontal disease has also been implemented in cytokine production,both topically and systemically. Hence, use of compositions of thepresent invention to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Finally, the compositions of the present invention may also be used totreat or prevent neurodegenerative disease selected from Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, frontotemporal lobar dementia, spinocerebellarataxia, dementia with Lewy bodies, cerebral ischemia orneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity or hypoxia.

In a preferred embodiment the compositions of the present invention maybe used to treat or prevent a disease selected from chronic or acuteinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn'sdisease, ulcerative colitis, multiple sclerosis and asthma.

Protein kinases are important enzymes involved in the regulation of manycellular functions. The LK6-serine/threonine-kinase gene of Drosophilamelanogaster was described as a short-lived kinase which can associatewith microtubules (J. Cell Sci. 1997, 110(2): 209-219). Genetic analysisin the development of the compound eye of Drosophila suggested a role inthe modulation of the RAS signal pathway (Genetics 2000 156(3):1219-1230). The closest human homologues of Drosophila LK6-kinase arethe MAP-kinase interacting kinase 2 (MNK2, e.g. the variants MNK2a andMNK2b) and MAP-kinase interacting kinase 1 (MNK1) and variants thereof.These kinases are mostly localized in the cytoplasm. MNKs arephosphorylated by the p42 MAP kinases Erk1 and Erk2 and the p38-MAPkinases. This phosphorylation is triggered in a response to growthfactors, phorbol esters and oncogenes such as Ras and Mos, and by stresssignaling molecules and cytokines. The phosphorylation of MNK proteinsstimulates their kinase activity towards eukaryotic initiation factor 4E(eIF4E) (EMBO J. 16: 1909-1920, 1997; Mol Cell Biol 19, 1871-1880, 1990;Mol Cell Biol 21, 743-754, 2001). Simultaneous disruption of both, theMNK1 and MNK2 gene in mice diminishes basal and stimulated eIF4Ephosphorylation (Mol Cell Biol 24, 6539-6549, 2004). Phosphorylation ofeIF4E results in a regulation of the protein translation (Mol Cell Biol22: 5500-5511, 2001).

There are different hypotheses describing the mode of the stimulation ofthe protein translation by MNK proteins. Most publications describe apositive stimulatory effect on the cap-dependent protein translationupon activation of MAP kinase-interacting kinases. Thus, the activationof MNK proteins can lead to an indirect stimulation or regulation of theprotein translation, e.g. by the effect on the cytosolic phospholipase 2alpha (BBA 1488:124-138, 2000).

WO 03/03762 discloses a link between human MNK genes, particularly thevariants of the human MNK2 genes, and diseases which are associated withthe regulation of body weight or thermogenesis. It is postulated thathuman MNK genes, particularly the MNK2 variants are involved in diseasessuch as e.g. metabolic diseases including obesity, eating disorders,cachexia, diabetes mellitus, hypertension, coronary heart disease,hypercholesterolemia, dyslipidemia, osteoarthritis, biliary stones,cancer of the genitals and sleep apnea, and in diseases connected withthe ROS defense, such as e.g. diabetes mellitus and cancer. WO 03/03762moreover discloses the use of nucleic acid sequences of the MAPkinase-interacting kinase (MNK) gene family and amino acid sequencesencoding these and the use of these sequences or of effectors of MNKnucleic acids or polypeptides, particularly MNK inhibitors andactivators in the diagnosis, prophylaxis or therapy of diseasesassociated with the regulation of body weight or thermogenesis.

WO 02/103361 describes the use of kinases 2a and 2b (MNK2a and MNK2b)interacting with the human MAP kinase in assays for the identificationof pharmacologically active ingredients, particularly useful for thetreatment of diabetes mellitus type 2. Moreover, WO 02/103361 disclosesalso the prophylaxis and/or therapy of diseases associated with insulinresistance, by modulation of the expression or the activity of MNK2a orMNK2b. Apart from peptides, peptidomimetics, amino acids, amino acidanalogues, polynucleotides, polynucleotide analogues, nucleotides andnucleotide analogues, 4-hydroxybenzoic acid methyl ester are describedas a substance which binds the human MNK2 protein.

First evidence for a role of MNKs in inflammation was provided bystudies demonstrating activation of MNK1 by proinflammatory stimuli. Thecytokines TNFα and IL-1β trigger the activation of MNK1 in vitro(Fukunaga and Hunter, EMBO J 16(8): 1921-1933, 1997) and induce thephosphorylation of the MNK-specific substrate eIF4E in vivo (Ueda etal., Mol Cell Biol 24(15): 6539-6549, 2004). In addition, administrationof lipopolysaccharide (LPS), a potent stimulant of the inflammatoryresponse, induces activation of MNK1 and MNK2 in mice, concomitant witha phosphorylation of their substrate eIF4E (Ueda et al., Mol Cell Biol24(15): 6539-6549, 2004).

Furthermore, MNK1 has been shown to be involved in regulating theproduction of proinflammatory cytokines. MNK1 enhances expression of thechemokine RANTES (Nikolcheva et al., J Clin Invest 110, 119-126, 2002).RANTES is a potent chemo-tractant of monocytes, eosinophils, basophilesand, natural killer cells. It activates and induces proliferation of Tlymphocytes, mediates degranulation of basophils and induces therespiratory burst in eosinophils (Conti and DiGioacchino, Allergy AsthmaProc 22(3):133-7, 2001).

WO 2005/003785 and Buxade et al., Immunity 23: 177-189, August 2005 bothdisclose a link between MNKs and the control of TNFα biosynthesis. Theproposed mechanism is mediated by a regulatory AU-rich element (ARE) inthe TNFα mRNA. Buxade et al. demonstrate proteins binding andcontrolling ARE function to be phosphorylated by MNK1 and MNK2.Specifically MNK-mediated phosphorylation of the ARE-binding proteinhnRNP A1 has been suggested to enhance translation of the TNFα mRNA.

TNFα is not the only cytokine regulated by an ARE. Functional AREs arealso found in the transcripts of several interleukins, interferones andchemokines (Khabar, J Interf Cytokine Res 25: 1-10, 2005). TheMNK-mediated phosphorylation of ARE-binding proteins has thus thepotential to control biosynthesis of cytokines in addition to that ofTNFα.

Current evidence demonstrates MNKs as down stream targets ofinflammatory signalling as well as mediators of the inflammatoryresponse. Their involvement in the production of TNFα, RANTES, andpotentially additional cytokines suggests inhibition of MNKs as strategyfor anti-inflammatory therapeutic intervention.

MNK1 and MNK2 (including all splice forms) phosphorylate the translationfactor eIF4E on Serine 209. MNK1/2 double knockout mice completely lackphosphorylation on Serine 209, indicating that MNK kinase are the onlykinases able to phosphorylate this site in vivo (Ueda et al., Mol CellBiol. 2004; 24(15):6539-49). eIF4E is overexpressed in a wide range ofhuman malignancies, and high eIF4E expression is frequently associatedwith more aggressive disease and poor prognosis. Furthermore, eIF4E canact as an oncogene when assayed in standard assays for oncogenicactivity (e.g. Ruggero et al., Nat Med. 2004 May; 10(5):484-6). eIF4Eexerts its oncogenic activity by stimulating the translation ofoncogenes such as c-myc and cyclinD1 (Culjkovic et al., J Cell Biol.2006; 175(3):415-26), by increasing the expression of pro-survivalfactors such as MCP-1 (Wendel et al., Genes Dev. 2007; 21(24):3232-7)and by positively regulating pathways of drug resistance (Wendel et al.,Nature 2004; 428(6980):332-7; Graff et al., Cancer Res. 2008;68(3):631-4; De Benedetti and Graff, Oncogene 2004; 23(18):3189-99;Barnhart and Simon, J Clin Invest. 2007; 117(9):2385-8). Suppression ofeIF4E expression by antisense oligonucleotides has shown promise inpreclinical experiments with human tumor cells (Graff et al., J ClinInvest. 2007; 117(9):2638-48). It has been shown that phosphorylation onSer209 is strictly required for the oncogenic activity of eIF4E in vitroand in vivo (Topisirovic et al., Cancer Res. 2004; 64(23):8639-42;Wendel et al., Genes Dev. 2007; 21(24):3232-7). Thus, inhibition of MNK1and MNK2 is expected to have beneficial effects in human malignancies.

Inhibitors of MNK (referred to as CGP57380 and CGP052088) have beendescribed (cf. Mol. Cell. Biol. 21, 5500, 2001; Mol Cell Biol Res Comm3, 205, 2000; Genomics 69, 63, 2000). CGP052088 is a staurosporinederivative having an IC₅₀ of 70 nM for inhibition of in vitro kinaseactivity of MNK1. CGP57380 is a low molecular weight selective,non-cytotoxic inhibitor of MNK2 (MNK2a or MNK2b) or of MNK1: Theaddition of CGP57380 to cell culture cells, transfected with MNK2 (MNK2aor MNK2b) or MNK1 showed a strong reduction of phosphorylated eIF4E.

WO 2007/147874 describes pyridine and pyrazine derivatives as MNK kinaseinhibitors. WO 2007/104053 describes 8-heteroarylpurines as MNK2inhibitors WO 2006/066937 discloses pyrazolopyrimidine compounds, and WO2006/136402 discloses certain thienopyrimidine compounds, both useful asMNK inhibitors.

DE 10 2007 024 470 and WO 2008/141843 disclose sulfoximine-substitutedquinoline and/or quinazoline derivatives which are claimed to act aserythropoietin-producing hepatoma amplified sequence-receptor kinaseinhibitors.

AIM OF THE PRESENT INVENTION

The aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare MNK1 and/or MNK2 inhibitors.

Another aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare potent and selective MNK1 and/or MNK2 inhibitors.

A further aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichhave an inhibiting effect on the kinase activity of MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variants thereof in vitroand/or in vivo and possess suitable pharmacological and pharmacokineticproperties to use them as medicaments.

A further aim of the present invention is to provide effective MNK1and/or MNK2 inhibitors, in particular for the treatment of metabolicdisorders, for example metabolic diseases, inflammatory diseases,cancer, neurodegenerative diseases and their consecutive complicationand disorders.

Still a further aim of the present invention is to provide effectiveMNK1 and/or MNK2 inhibitors, in particular for the treatment ofmetabolic disorders, for example diabetes, dyslipidemia and/or obesityand their consecutive complication and disorders.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/orvariants thereof in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of new compounds, in particular sulfoximine substitutedquinazoline derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

OBJECT OF THE INVENTION

It has now been found that the compounds according to the inventiondescribed in more detail hereinafter have surprising and particularlyadvantageous properties, in particular as MNK1 and/or MNK2 inhibitors.

The present invention concerns compounds of the general formula I:

whereinAr is selected from the group Ar-G1 consisting of:

-   -   wherein X is CH or N;    -   R³ is H, halogen, CN or —C(═O)—NH₂; and    -   R⁴ is selected from the group R⁴-G1 consisting of:

-   -   wherein    -   is a single or a double bond;    -   n is 0 or 1;    -   Y is O or NR^(N1);    -   R^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,        —C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)₁₋₃-phenyl and —SO₂—C₁₋₃-alkyl;    -   R⁷ is selected from the group consisting of F, CN, OH,        —O—(C₁₋₃-alkyl), —O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl),        —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and —O—C(O)—C₁₋₄-alkyl; and    -   R⁹ is H or R⁹ together with R⁷ form —CH₂— or —(CH₂)₂—;        -   wherein each alkyl group mentioned in the definition of            R^(N1) and R⁷ is optionally substituted with one or more F            or —O—(C₁₋₃-alkyl);            R¹ is selected from the group R¹-G1 consisting of:

-   -   wherein    -   R⁵ is selected from the group consisting of C₁₋₅-alkyl,        C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,        heteroaryl, and aryl,        -   wherein each alkyl group of R⁵ is optionally substituted            with one or more F or with one —O—(C₁₋₃-alkyl),            —O—C₃₋₇-cycloalkyl, —O-heterocyclyl, C₃₋₇-cycloalkyl,            heterocyclyl or phenyl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F,    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 3 to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O, S and NR^(N2),        -   wherein R^(N2) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl),            —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or            —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with halogen, CN, OH,        C₁₋₃-alkyl or —O—(C₁₋₃-alkyl); and        R² is selected from the group R²-G1 consisting of halogen, CN,        OH, C₁₋₃-alkyl, C₃₋₅-cycloalkyl and —O—(C₁₋₃-alkyl), wherein        each alkyl group is optionally substituted with one or more F;        and        R^(x) is H or halogen; and    -   wherein, if not otherwise specified, each alkyl group in the        above definitions is linear or branched and may be substituted        with one to three F;        including any tautomers and stereoisomers thereof,        or a salt thereof,        or a solvate or hydrate thereof.

If not specified otherwise, any alkyl moiety mentioned in thisapplication may be straight-chained or branched and may be substitutedwith one to three F.

In a further aspect the present invention relates to processes forpreparing a compound of general formula I and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula I according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are influenced by the inhibition of thekinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)and/or variants thereof in a patient in need thereof characterized inthat a compound of general formula I or a pharmaceutically acceptablesalt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition influenced by the inhibition of the kinase activityof MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variantsthereof in a patient that includes the step of administering to thepatient in need of such treatment a therapeutically effective amount ofa compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are influenced by theinhibition of the kinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2(MNK2a or MNK2b) and/or variants thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly Ar, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(X), R^(N1)and R^(N2) are defined as above and hereinafter. If residues,substituents, or groups occur several times in a compound, they may havethe same or different meanings. Some preferred meanings of individualgroups and substituents of the compounds according to the invention willbe given hereinafter. Any and each of these definitions may be combinedwith each other.

Ar:

Ar-G1:

According to one embodiment, the group Ar is selected from the groupAr-G1 as defined hereinbefore and hereinafter.

Ar-G2:

According to another embodiment, the group Ar is selected from the groupAr-G2 consisting of:

wherein X is CH or N;R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G3:

According to another embodiment, the group Ar is selected from the groupAr-G3 consisting of:

wherein X is CH or N;R³ is H, F or Cl; andR⁴ is as defined hereinbefore or hereinafter.Ar-G4:

According to another embodiment, the group Ar is selected from the groupAr-G4 consisting of:

wherein R³ is H or Cl; andR⁴ is as defined hereinbefore or hereinafter.Ar-G5:

According to another embodiment, the group Ar is selected from the groupAr-G5 consisting of:

wherein R⁴ is as defined hereinbefore or hereinafter.Ar-G6:

According to another embodiment, the group Ar is selected from the groupAr-G6 consisting of:

wherein R³ is F or Cl; andR⁴ is as defined hereinbefore or hereinafter.Ar-G7:

According to another embodiment, the group Ar is selected from the groupAr-G7 consisting of:

wherein R³ is F; andR⁴ is as defined hereinbefore or hereinafter.

According to another embodiment, the group Ar is selected from the groupconsisting of

R⁴:R⁴-G1:

According to one embodiment, the group R⁴ is selected from the groupR⁴-G1 as defined hereinbefore and hereinafter.

R⁴-G2:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G2 consisting of:

-   -   wherein    -   is a single or a double bond;    -   n is 0 or 1;    -   Y is O or NR^(N1);    -   R^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,        —C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)₁₋₃-phenyl and —SO₂—C₁₋₃-alkyl;        and    -   R⁷ is selected from the group consisting of F, CN, OH,        —O—(C₁₋₃-alkyl), —O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl),        —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and —O—C(O)—C₁₋₄-alkyl;        -   wherein each alkyl group mentioned in the definition of            R^(N1) and R⁷ is optionally substituted with one or more F            or —O—(C₁₋₃-alkyl).            R⁴-G2a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G2a consisting of:

-   -   wherein    -   is a single or a double bond;    -   n is 0 or 1;    -   Y is O or NR^(N1);    -   R^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,        —C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)₁₋₃-phenyl and —SO₂—C₁₋₃-alkyl;        and    -   R⁷ is selected from the group consisting of F, CN, OH,        —O—(C₁₋₃-alkyl), —O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl),        —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and —O—C(O)—C₁₋₄-alkyl;        -   wherein each alkyl group mentioned in the definition of            R^(N1) and R⁷ is optionally substituted with one or more F            or —O—(C₁₋₃-alkyl).            R⁴-G3:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G3 consisting of:

whereinR^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,—C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)-phenyl and —SO₂—C₁₋₃-alkyl;R⁷ is selected from the group consisting of F, CN, OH, —O—(C₁₋₃-alkyl),—O—(CH₂)—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and—O—C(O)—C₁₋₄-alkyl; andR^(7a) is selected from the group consisting of OH and —O—(C₁₋₃-alkyl),

-   -   wherein each alkyl group mentioned in the definition of R^(N1),        R⁷ and R^(7a) is optionally substituted with one or more F or        one —O—(C₁₋₃-alkyl).        R⁴-G3a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G3a consisting of:

whereinR^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,—C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)-phenyl and —SO₂—C₁₋₃-alkyl;R⁷ is selected from the group consisting of F, CN, OH, —O—(C₁₋₃-alkyl),—O—(CH₂)—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and—O—C(O)—C₁₋₄-alkyl; andR^(7a) is selected from the group consisting of OH and —O—(C₁₋₃-alkyl),

-   -   wherein each alkyl group mentioned in the definition of R^(N1),        R⁷ and R^(7a) is optionally substituted with one or more F or        one —O—(C₁₋₃-alkyl).        R⁴-G4:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4 consisting of:

whereinR^(N1) is selected from the group consisting of H, C₁₋₃-alkyl, —C(O)—CH₃and —SO₂—CH₃;R⁷ is selected from the group consisting of F, CN, OH, —O—(C₁₋₃-alkyl)and —O—(CH₂)-cyclopropyl; andR^(7a) is selected from the group consisting of OH and —O—CH₃,

-   -   wherein each alkyl group mentioned in the definition of R^(N1),        R⁷ and R^(7a) is optionally substituted with one or more F or        one —O—CH₃.        R⁴-G4a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4a consisting of:

whereinR⁷ is selected from the group consisting of F, CN, OH and—O—(C₁₋₃-alkyl),

-   -   wherein each alkyl group mentioned in the definition of R⁷ is        optionally substituted with one to three F or one —O—CH₃.        R⁴-G4b:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4b consisting of:

whereinR^(N1) is selected from the group consisting of H, C₁₋₃-alkyl, —C(O)—CH₃and —SO₂—CH₃; andR⁷ is selected from the group consisting of OH and —O—CH₃,

-   -   wherein the alkyl group mentioned in the definition of R^(N1)        and the CH₃ group mentioned in the definition of R⁷ are        optionally substituted with one to three F.        R⁴-G5:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5 consisting of:

whereinR^(N1) is selected from the group consisting of H, CH₃ and —SO₂—CH₃; andR⁷ and R^(7a) are selected from the group consisting of OH and—O—(C₁₋₃-alkyl),

-   -   wherein the —O-alkyl group mentioned in the definition of R⁷ is        optionally substituted with one to three F.        R⁴-G5a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5a consisting of:

wherein R⁷ is selected from the group consisting of OH and—O—(C₁₋₃-alkyl),

-   -   wherein the —O-alkyl group is optionally substituted with one to        three F.        R⁴-G5b:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5b consisting of:

whereinR^(N1) is CH₃ or —SO₂—CH₃; andR⁷ is OH.R⁴-G5c:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5c consisting of:

whereinR^(7a) is selected from the group consisting of OH and —O—CH₃.R⁴-G6:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G6 consisting of:

wherein R⁷ is OH or —O—CH₃.

According to one embodiment, the substituents of the R⁴-ring system arein the trans-Position.

According to another embodiment, the substituents of the R⁴-ring systemare in the cis-Position.

According to another embodiment, the group R⁴ is selected from the groupconsisting of:

R¹:R¹-G1:

According to one embodiment, the group R¹ is selected from the groupR¹-G1 as defined hereinbefore and hereinafter.

R¹-G2:

According to another embodiment, the group R¹ is selected from the groupR¹-G2 consisting of:

wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,C₃₋₇-cycloalkyl, tetrahydropyranyl, pyridinyl and phenyl,

-   -   wherein each alkyl group is optionally substituted with one or        more F or with one —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl,        C₃₋₇-cycloalkyl or phenyl; and        R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F;        or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 3- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O, S and NR^(N2),    -   wherein R^(N2) is H or C₁₋₃-alkyl;    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with F, Cl, Br, CN, OH,        —O—(C₁₋₃-alkyl), C₁₋₃-alkyl.        R¹-G3:

According to another embodiment, the group R¹ is selected from the groupR¹-G3 consisting of:

wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl,

-   -   wherein the alkyl group is optionally substituted with one to        three F or with one —O—CH₃ or phenyl; and        R⁶ is C₁₋₃-alkyl which is optionally substituted with one to        three F;        or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4-, 5- or 6-membered saturated heterocycle        that is optionally substituted with OH or CH₃.        R¹-G3a:

According to another embodiment, the group R¹ is selected from the groupR¹-G3a consisting of:

wherein R⁵ is of C₁₋₄-alkyl, cyclopropyl, tetrahydropyranyl, pyridinylor phenyl; and R⁶ is methyl.R¹-G3aa:

According to another embodiment, the group R¹ is selected from the groupR¹-G3aa consisting of:

wherein R⁵ is methyl or ethyl; andR⁶ is methyl.R¹-G3b:

According to another embodiment, the group R¹ is selected from the groupR¹-G3b consisting of:

wherein R⁵ and R⁶ together with the sulfur atom to which they areattached form a 4-, 5- or 6-membered saturated heterocycle that isoptionally substituted with OH or CH₃.R¹-G4:

According to another embodiment, the group R¹ is selected from the groupR¹-G4 consisting of:

wherein R⁵ is C₁₋₄-alkyl, which is optionally substituted with one ormore F;R⁶ is CH₃ which is optionally substituted with one to three F; andR⁸ is H, OH or CH₃.R¹-G5:

According to another embodiment, the group R¹ is selected from the groupR¹-G5 consisting of:

R¹-G6:

According to another embodiment, the group R¹ is selected from the groupR¹-G6 consisting of:

R¹-G7:

According to another embodiment, the group R¹ is selected from the groupR¹-G7 consisting of:

R²:R²-G1:

According to one embodiment, the group R² is selected from the groupR²-G1 as defined hereinbefore and hereinafter.

R²-G2:

According to another embodiment, the group R² is selected from the groupR²-G2 consisting of F, Cl, Br, CN, C₁₋₃-alkyl, C₃₋₅-cycloalkyl and—O—(C₁₋₃-alkyl), wherein each alkyl group is optionally substituted withone to three F.

R²-G3:

According to another embodiment, the group R² is selected from the groupR²-G3 consisting of F, Cl, Br, CH₃, CF₃, cyclopropyl and—O—(C₁₋₂-alkyl), wherein each alkyl group is optionally substituted withone to three F.

R²-G4:

According to another embodiment, the group R² is selected from the groupR²-G4 consisting of F, Cl, Br, CH₃, CF₃, —O—CH₃ and —O—CH₂CH₃.

R²-G5:

According to another embodiment, the group R² is selected from the groupR²-G5 consisting of F, Cl, CH₃ and —O—CH₃.

R²-G6:

According to another embodiment, the group R² is selected from the groupR²-G6 consisting of CH₃.

R^(X):

R^(X)-G1:

According to one embodiment, the group R^(X) is selected from the groupR^(X)-G1 as defined hereinbefore and hereinafter.

R^(X)-G2:

According to another embodiment, the group R^(X) is selected from thegroup R^(X)-G2 consisting of H and F.

R^(X)-G3:

According to another embodiment, the group R^(X) is selected from thegroup R^(X)-G3 consisting of H.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1 to I.4, wherein any tautomers andstereoisomers, solvates, hydrates and salts thereof, in particular thepharmaceutically acceptable salts thereof, are encompassed.

wherein the variables R¹, R², R³, R⁴, X and Ar are defined ashereinbefore and hereinafter.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions set forth hereinbefore:

Embodiment Ar R⁴ R¹ R² R^(x) E-1 Ar-G1 R⁴-G1 R¹-G1 R²-G1 R^(x)-G1 E-2Ar-G2 R⁴-G2 R¹-G2 R²-G2 R^(x)-G2 E-3 Ar-G3 R⁴-G2 R¹-G2 R²-G3 R^(x)-G3E-4 Ar-G3 R⁴-G2 R¹-G3 R²-G3 R^(x)-G2 E-5 Ar-G3 R⁴-G2 R¹-G3a R²-G3R^(x)-G2 E-6 Ar-G3 R⁴-G2 R¹-G3aa R²-G3 R^(x)-G2 E-7 Ar-G3 R⁴-G2 R¹-G3bR²-G3 R^(x)-G2 E-8 Ar-G3 R⁴-G2 R¹-G4 R²-G3 R^(x)-G2 E-9 Ar-G3 R⁴-G2R¹-G5 R²-G3 R^(x)-G2 E-10 Ar-G3 R⁴-G2 R¹-G6 R²-G3 R^(x)-G2 E-11 Ar-G3R⁴-G2 R¹-G7 R²-G3 R^(x)-G2 E-12 Ar-G3 R⁴-G2a R¹-G2 R²-G2 R^(x)-G2 E-13Ar-G3 R⁴-G2a R¹-G2 R²-G3 R^(x)-G3 E-14 Ar-G3 R⁴-G2a R¹-G3 R²-G3 R^(x)-G2E-15 Ar-G3 R⁴-G2a R¹-G3a R²-G3 R^(x)-G2 E-16 Ar-G3 R⁴-G2a R¹-G3aa R²-G3R^(x)-G2 E-17 Ar-G3 R⁴-G2a R¹-G3b R²-G3 R^(x)-G2 E-18 Ar-G3 R⁴-G2a R¹-G4R²-G3 R^(x)-G2 E-19 Ar-G3 R⁴-G2a R¹-G5 R²-G3 R^(x)-G2 E-20 Ar-G3 R⁴-G2aR¹-G6 R²-G3 R^(x)-G2 E-21 Ar-G3 R⁴-G2a R¹-G7 R²-G3 R^(x)-G2 E-22 Ar-G4R⁴-G4b R¹-G7 R²-G5 R^(x)-G3 E-23 Ar-G4 R⁴-G5a R¹-G7 R²-G5 R^(x)-G3 E-24Ar-G5 R⁴-G4b R¹-G7 R²-G5 R^(x)-G3 E-25 Ar-G5 R⁴-G5a R¹-G7 R²-G5 R^(x)-G3E-26 Ar-G6 R⁴-G3 R¹-G3 R²-G3 R^(x)-G2 E-27 Ar-G6 R⁴-G3 R¹-G5 R²-G3R^(x)-G3 E-28 Ar-G6 R⁴-G3a R¹-G3 R²-G4 R^(x)-G3 E-29 Ar-G6 R⁴-G4 R¹-G5R²-G4 R^(x)-G3 E-30 Ar-G6 R⁴-G5 R¹-G6 R²-G4 R^(x)-G3 E-31 Ar-G6 R⁴-G6R¹-G7 R²-G4 R^(x)-G3 E-32 Ar-G7 R⁴-G3 R¹-G3 R²-G3 R^(x)-G2 E-33 Ar-G7R⁴-G3 R¹-G5 R²-G3 R^(x)-G3 E-34 Ar-G7 R⁴-G3a R¹-G3 R²-G4 R^(x)-G3 E-35Ar-G7 R⁴-G4 R¹-G5 R²-G4 R^(x)-G3 E-36 Ar-G7 R⁴-G5 R¹-G6 R²-G4 R^(x)-G3E-37 Ar-G7 R⁴-G6 R¹-G7 R²-G4 R^(x)-G3

One embodiment of the invention concerns those compounds of formula I,wherein

Ar is selected from the group Ar-G3 consisting of:

wherein X is CH or N;R³ is H, F or Cl; and; andR⁴ is selected from the group R⁴-G3 consisting of:

-   -   wherein    -   R^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,        —C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)-phenyl and —SO₂—C₁₋₃-alkyl;    -   R⁷ is selected from the group consisting of F, CN, OH,        —O—(C₁₋₃-alkyl), —O—(CH₂)—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl,        —O-oxetanyl and —O—C(O)—C₁₋₄-alkyl; and    -   R^(7a) is selected from the group consisting of OH and        —O—(C₁₋₃-alkyl),        -   wherein each alkyl group mentioned in the definition of            R^(N1), R⁷ and R^(7a) is optionally substituted with one or            more F or one —O—(C₁₋₃-alkyl);            R¹ is selected from the group R¹-G3 consisting of:

wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl,

-   -   wherein the alkyl group is optionally substituted with one to        three F or with one —O—CH₃ or phenyl; and        R⁶ is C₁₋₃-alkyl which is optionally substituted with one to        three F;        or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4-, 5- or 6-membered saturated heterocycle        that is optionally substituted with OH or CH₃;        R² is selected from the group R²-G3 consisting of F, Cl, Br,        CH₃, CF₃, cyclopropyl and —O—(C₁₋₂-alkyl), wherein each alkyl        group is optionally substituted with one to three F; and        R^(X) is selected from the group R^(X)-G2 consisting of H and F;        and the pharmaceutically acceptable salts thereof.

Another embodiment of the invention concerns those compounds of formulaI, wherein

Ar is selected from the group consisting of

R¹ is selected from the group R¹-G6 consisting of:

R² is selected from the group R²-G5 consisting of F, Cl, CH₃ and —O—CH₃;andR^(X) is selected from the group R^(X)-G3 consisting of H;and the pharmaceutically acceptable salts thereof.

Preferred examples for compounds of formula I are:

and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis.Preferably the compounds are obtained analogously to the methods ofpreparation explained more fully hereinafter, in particular as describedin the experimental section. In some cases the sequence adopted incarrying out the reaction schemes may be varied. Variants of thesereactions that are known to one skilled in the art but are not describedin detail here may also be used. The general processes for preparing thecompounds according to the invention will become apparent to a personskilled in the art on studying the schemes that follow. Startingcompounds are commercially available or may be prepared by methods thatare described in the literature or herein, or may be prepared in ananalogous or similar manner. Before the reaction is carried out anycorresponding functional groups in the compounds may be protected usingconventional protecting groups. These protecting groups may be cleavedagain at a suitable stage within the reaction sequence using methodsfamiliar to a person skilled in the art.

Typical methods of preparing the compounds of the invention aredescribed in the experimental section.

The potent inhibitory effect of the compounds of the invention can bedetermined by in vitro enzyme assays as described in the experimentalsection.

The compounds of the present invention may also be made by methods knownin the art including those described below and including variationswithin the skill of the art.

Compounds of the general formula 1-3, wherein X, R³ and R⁴ are aspreviously defined, can be prepared via the process outlined in Scheme 1using a compound of the general formula 1-1, wherein X and R³ are aspreviously defined, with an alcohol of the general formula 1-2, whereinR⁴ is as previously defined, in presence of a base in appropriatesolvents such as THF or DMF at a temperature between 0° C. and 150° C.As base sodium hydride or lithium hexamethyldisilazane may be used.Hydrogenation of a compound of the general formula 1-3, wherein X, R³and R⁴ are as previously defined, in order to obtain a compound of thegeneral formula 1-4, wherein X, R³ and R⁴ are as previously defined, maybe achieved in the presence of hydrogen and a catalyst such as palladiumor Raney nickel in an appropriate solvent. Hydrogen can be introduced asa gas or stem from a hydrogen source such as ammonium formate.

In Scheme 2 compounds of the general formula 2-3, wherein X, R³ and R⁴are as previously defined, may be obtained by Mitsunobu reaction of acompound with the general formula 2-1, wherein X, R³ are as previouslydefined, with an alcohol of the general formula 2-2, wherein R⁴ is aspreviously defined, in the presence of triphenylphosphine and andialkylazodicarboxylate such as diethylazodicarboxylate,diisopropylazodicarboxylate or di-tert.butylazodiacarboxylate in asolvent such as THF at temperatures between −10° C. and 80° C.,preferrably between 0° C. and 30° C.

4,5,7-substituted or 4,5,6,7-substituted quinazolines of the generalformula 3-4, wherein X, R¹, R², R³, R⁴ and R^(x) are as previouslydefined, may be prepared as shown in scheme 3. Substitutedantranilonitriles of the general formula 3-1, wherein R¹, R² and R^(x)are as previously defined, may react with N,N-dimethylformamide dimethylacetal under reflux. The resulting formamidines of the general formula3-2, wherein R¹, R² and R^(x) are as previously defined, may becondensed with primary aromatic amines of the general formula 3-3,wherein X, R³ and R⁴ are as previously defined, in acetic acid (J. Med.Chem., 2010, 53 (7), 2892-2901). Dioxane can be used as cosolvent inthis reaction.

The sulphoximine-substituent of the general formula 4-3, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 4 byPd or Cu-catalyzed coupling reactions from the corresponding boronicacid derivatives of the general formula 4-2, wherein R² and R^(x) are aspreviously defined.

The boronic esters of the general formula 4-2, wherein R² and R^(x) areas previously defined, may be prepared using a Ir-catalyzed boronylationreaction (Chem. Rev., 2010, 110 (2), 890-931) and coupled with thesulphoximine of the general formula 4-3, wherein R⁵ and R⁶ are aspreviously defined, under Cu-catalysis in a suitable solvent like MeOH(Org. Lett., 2005, 7 (13), 2667-2669).

The sulphoximine-substituent of the general formula 5-2, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 5 byPd or Cu-catalyzed coupling reactions from the corresponding bromoderivatives of the general formula 5-1 or 5-4, wherein Ar and R² are aspreviously defined.

For the palladium catalyzed coupling one of the following reactionconditions may be used: Pd(OAc)₂, BINAP, Cs₂CO₃ in toluene as solvent(J. Org. Chem., 2000, 65 (1), 169-175), or Pd₂dba₃,2-(di-t-butylphosphino) biphenyl, NaO^(t)Bu in dioxane or DMF as solvent(cf. WO 2008/141843 A1).

In case the R²-substituent of compounds of the general formula 6-2 or6-4 in Scheme 6, wherein Ar, R², R⁵ and R⁶ are as previously defined, islinked via a nitrogen, oxygen or sulphur atom to the ring system, thecorresponding substituent R² may be introduced by nucleophilic aromaticsubstitution from the aryl fluoride of the general formula 6-1 or 6-3,wherein Ar, R⁵ and R⁶ are as previously defined, using a suitable basein an inert solvent like Cs₂CO₃ in dioxane or NaH, LiHMDS or DIPEA inNMP.

As shown in Scheme 7, the sulphoximines of the general formula 7-2,wherein R⁵ and R⁶ are as previously defined, may be prepared from thecorresponding sulphoxides of the general formula 7-1, wherein R⁵ and R⁶are as previously defined, by reaction with sodium azide and sulfuricacid (H₂SO₄). A suitable solvent like dichloromethane maybe used.

Alternatively, sulfoximines of the general formula 7-2, wherein R⁵ andR⁶ are as previously defined, may be prepared from the correspondingsulphoxides of the general formula 7-1, wherein R⁵ and R⁶ are aspreviously defined, by reaction with o-mesitylenesulphonylhydroxylamine(MSH) in presence of a suitable solvent like dichloromethane.

As shown in scheme 8, sulphoxides of the general formula 8-1, wherein R⁵and R⁶ are as previously defined, may be reacted with trifluoroacetamidein presence of PhI(OAc)₂, Rh₂(OAc)₄, and MgO in a suitable solvent likedichloromethane to form compounds of the general formula 8-2, wherein R⁵and R⁶ are as previously defined.

Sulfoximines of the general formula 8-3, wherein R⁵ and R⁶ are aspreviously defined, may be prepared by saponification of compounds ofthe general formula 8-2, wherein R⁵ and R⁶ are as previously defined(Org. Lett., 2004, 6 (8), 1305-1307). Alternatively, other suitableprotecting groups and Iron as catalyst can be utilized (Org. Lett.,2006, 8 (11), 2349-2352).

In scheme 9 a general synthesis of sulfoximines of the general formula9-5, wherein R⁵ and R⁶ are as previously defined, is described.

Starting from the thioethers of the general formula 9-1, wherein R⁵ andR⁶ are as previously defined, the corresponding N-cyano sulfilimines ofthe general formula 9-2, wherein R⁵ and R⁶ are as previously defined,maybe prepared by reaction with cyanamide in the presence of a base likeNaO^(t)Bu or KO^(t)Bu and NBS or I₂ in a suitable solvent like methanol.The sulfilimines of the general formula 9-2, wherein R⁵ and R⁶ are aspreviously defined, are oxidized to the N-cyanosulfoximines of thegeneral formula 9-3, wherein R⁵ and R⁶ are as previously defined. Afterremoval of the N-cyano group the N-trifluoroacetylsulfoximines of thegeneral formula 9-4, wherein R⁵ and R⁶ are as previously defined, may beobtained. After removal of the trifluoroacetyl moiety the NH-freesulfoximines of the general formula 9-5, wherein R⁵ and R⁶ are aspreviously defined, can be obtained (Org. Lett., 2007, 9 (19),3809-3811).

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula I”, “compound(s) of the invention” and the like denote thecompounds of the formula I according to the present invention includingtheir tautomers, stereoisomers and mixtures thereof and the saltsthereof, in particular the pharmaceutically acceptable salts thereof,and the solvates and hydrates of such compounds, including the solvatesand hydrates of such tautomers, stereoisomers and salts thereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionof the particular disease or condition, (ii) attenuation, amelioration,or elimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex)” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo-, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking pharmaceutically acceptable acid or base salts thereof.

Salts of acids which are useful, for example, for purifying or isolatingthe compounds of the present invention are also part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example, the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer from 2 to n, eitheralone or in combination with another radical, denotes an acyclic,straight-chain or branched divalent alkyl radical containing from 1 to ncarbon atoms. For example, the term C₁₋₄-alkylene includes —(CH₂)—,—(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C≡CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C≡CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cycloalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cycloalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term bicyclic includes spirocyclic.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl and morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

-   -   R^(N)═H or residue attached via a C atom

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The biological activity of compounds was determined by the followingmethods:

A. MNK2a In Vitro Kinase Assay (Assay 1)

The MNK2a in vitro kinase assay is described in detail in WO2011/104340.

ASSAY SETUP: The inhibition of kinase activity of MNK2a was assessedusing pre-activated GST-MNK2a. The kinase reaction contains 24 μMsubstrate peptide (NH₂-TATKSGSTTKNR-CONH₂, differing from Seq. ID No. 5of WO 2011/104340 by the C-terminal —CONH₂ group), 20 μM ATP, 14 nMligand and 2 nM pre-activated MNK2a. The reaction buffer conditions are16 mM HEPES/KOH pH 7.4, 8 mM MgCl₂, 0.4 mM DTT, 0.08% (w/v) bovine serumalbumin (BSA, Sigma, Germany, cat. no. A3059), 0.008% (w/v) PluronicF127 (Sigma, Germany, cat. no. P2443), 3% (v/v) DMSO (Applichem,Germany, cat. no. A3006). The kinase reaction is at room temperature for60 min. The kinase reaction is terminated by addition of 0.67 reactionvolumes of 1 μM antibody in 20 mM HEPES/KOH pH 7.4, 50 mMethylenediaminetetraacetic acid, disodium salt (EDTA, Sigma, Germany,cat. no. E5134), 0.5 mM DTT, 0.05% (w/v) polyoxyethylene-sorbitanmonolaureate (Tween 20, Sigma, Germany, cat. no. P7949). After 1 hequilibration time at room temperature, samples are subjected tofluorescence polarization measurement. The fluorescence polarizationreadout was generated on an Envision multimode reader (PerkinElmer)equipped with a FP Dual Emission filter and mirror set (PerkinElmer2100-4260). Excitation filter 620 nm, S and P polarized emission filters688 nM.

B. MNK2a In Vitro Kinase Assay (Assay 2)

ASSAY SETUP: The inhibition of kinase activity of MNK2a was assessedusing pre-activated GST-MNK2a. The white, 384-well OptiPlate F plateswere purchased from PerkinElmer. The ADP-Glo Kinase Assay (includingultra pure ATP) was purchased from Promega (V9103). Activated MNK2a wasobtained as described in WO2011/104340. The unlabeled eIF4E peptide(NH₂-TATKSGSTTKNR-CONH₂), differing from Seq. ID No. 5 of WO 2011/104340by the C-terminal —CONH₂ group, was purchased from Thermo FisherScientific. All other materials were of highest grade commerciallyavailable. Compounds are tested in either serial dilutions or singledose concentrations. The compound stock solutions are 10 mM in 100% DMSOThe serial compound dilutions are prepared in 100% DMSO followed by1:27.3 intermediate dilution in assay buffer. The final DMSOconcentration in assay will be <3%.

In the 384-well plates 3 μl of test compound from the intermediatedilutionis mixed with 4 μl of the activated MNK2 enzyme (finalconcentration of 10 nM) and 4 μl of the peptide (final concentration of25 μM)/ultra pure ATP (final concentration of 20 μM), all dissolved inassay buffer. This step is followed by an incubation time of 90 min,then 10 μl of ADP Glo reagent are added, followed by 40 min ofincubation. Then 20 μl of kinase detection reagent are admixed. Theplates are sealed and after an incubation period of 30 min, theluminescence signal is measured in an Envision reader to determine theamount of produced ADP. All incubation steps are performed at roomtemperature.

The assay buffer consists of 20 mM HEPES, 2 mM DTT, 0.01% BSA, 20 mMMgCl₂ and 0.1% Pluronic F-127.

Each assay microtiter plate contains wells with vehicle controls insteadof compound (1% DMSO in water) as reference for the high signal (100%CTL, high signal), and wells containing a potent MNK2 inhibitor (final20 μM, 1% DMSO) as reference for low signal (0% CTL, low signal).

The luminescent signal generated is proportional to the ADPconcentration produced and is correlated with activated MNK2 activity.The analysis of the data is performed by the calculation of thepercentage of ATP consumption of activated MNK2 in the presence of thetest compound compared to the consumption of ATP in the presence ofactivated MNK2 without compound.RLU(sample)−RLU(low control))*100/(RLU(high value)−RLU(low control))[RLU=relative luminescence units]

An inhibitor of the MNK2 enzyme will give values between 100% CTL (noinhibition) and 0% CTL (complete inhibition). Values of more than 100%CTL are normally related to compound/sample specific physico-chemicalproperties (e.g. solubility, light absorbance, fluorescence).

IC50 values based on dose response curves are calculated with theAssayExplorer software.

C. MNK1 In Vitro Kinase Assay (Assay 3)

MNK1 Data can be obtained from the MNK1 Z′-LYTE® assay. The MNK1Z′-LYTE® screening protocol and assay conditions are also described onwww.invitrogen.com.

The assay is described as follows:

The Z′-LYTE® biochemical assay employs a fluorescence-based,coupled-enzyme format and is based on the differential sensitivity ofphosphorylated and non-phosphorylated peptides to proteolytic cleavage.The peptide substrate is labeled with two fluorophores—one at eachend—that make up a FRET pair.

In the primary reaction, the kinase transfers the gamma-phosphate of ATPto a single tyrosine, serine or threonine residue in a syntheticFRET-peptide. In the secondary reaction, a site-specific proteaserecognizes and cleaves non-phosphorylated FRET-peptides. Phosphorylationof FRET-peptides suppresses cleavage by the Development Reagent.Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor(i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved,phosphorylated FRET-peptides maintain FRET. A ratiometric method, whichcalculates the ratio (the Emission Ratio) of donor emission to acceptoremission after excitation of the donor fluorophore at 400 nm, is used toquantitate reaction progress, as shown in the equation below.Emission Ratio=Coumarin Emission (445 nm)/Fluorescein Emission (520 nm)

ASSAY SETUP: The inhibition of kinase activity of MNK1a was assessedusing pre-activated GST-MNK1a. The 2×MKNK1 (MNK1) mixture is prepared in50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 4 mM MnCl₂, 1 mM EGTA, 2mM DTT. The final 10 μL Kinase Reaction consists of 13.5-54 ng MKNK1(MNK1) and 2 μM Ser/Thr 07 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl₂, 2 mM MnCl₂, 1 mM EGTA, 1 mM DTT. After the 1 hour Kinase Reactionincubation, 5 μL of a 1:32768 dilution of Development Reagent A isadded.

Assay Conditions

Test Compounds:

The Test Compounds are screened in 1% DMSO (final) in the well.

Peptide/Kinase Mixtures:

All Peptide/Kinase Mixtures are diluted to a 2× working concentration inthe MNK1 Kinase Buffer.

ATP Solution:

All ATP Solutions are diluted to a 4× working concentration in KinaseBuffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA).

Development Reagent Solution:

The Development Reagent is diluted in Development Buffer

Assay Protocol:

Bar-Coded Corning, Low Volume NBS, 384-Well Plate (Corning Cat. #3676)

1. 2.5 μL—4× Test Compound

2. 5 μL—2× Peptide/Kinase Mixture

3. 2.5 μL—4×ATP Solution

4. 30-second plate shake

5. 60-minute Kinase Reaction incubation at room temperature

6. 5 μL—Development Reagent Solution

7. 30-second plate shake

8. 60-minute Development Reaction incubation at room temperature

9. Read on fluorescence plate reader and analyze the data

Data Analysis

The following equations are used for each set of data points:FI_(Sample)−FI_(TCFI Ctl)  Correction for Background Fluorescence:Coumarin Emission (445 nm)/Fluorescein Emission (520 nm)  Emission Ratio(using values corrected for background fluorescence):1−((Emission Ratio×F _(100%))−C _(100%))/((C _(0%) −C _(100%))+[EmissionRatio×(F _(100%) −F _(0%))])*100  % Phosphorylation (% Phos):1−(% Phos_(Sample)/% Phos_(0% Inhibition Ctl))*100  % Inhibition:FI=Fluorescence IntensityC_(100%)=Average Coumarin emission signal of the 100% Phos. ControlC_(0%)=Average Coumarin emission signal of the 0% Phos. ControlF_(100%)=Average Fluorescein emission signal of the 100% Phos. ControlF_(0%)=Average Fluorescein emission signal of the 0% Phos. ControlGraphing Software

SelectScreen® Kinase Profiling Service uses XLfit from IDBS. The doseresponse curve is curve fit to model number 205 (sigmoidal dose-responsemodel). If the bottom of the curve does not fit between −20% & 20%inhibition, it is set to 0% inhibition. If the top of the curve does notfit between 70% and 130% inhibition, it is set to 100% inhibition. Theactivity of MNK proteins can be assayed also by other in vitro kinaseassay formats. For example, suitable kinase assays have been describedin the literature in Knauf et al., Mol Cell Biol. 2001 August;21(16):5500-11 or in Scheper et al., Mol Cell Biol. 2001 February;21(3):743-54. In general, MNK kinase assays can be performed such that aMNK substrate such as a protein or a peptide, which may or may notinclude modifications as further described below, or others arephosphorylated by MNK proteins having enzymatic activity in vitro. Theactivity of a candidate agent can then be determined via its ability todecrease the enzymatic activity of the MNK protein. The kinase activitymay be detected by change of the chemical, physical or immunologicalproperties of the substrate due to phosphorylation.

In one example, the kinase substrate may have features, designed orendogenous, to facilitate its binding or detection in order to generatea signal that is suitable for the analysis of the substratesphosphorylation status. These features may be, but are not limited to, abiotin molecule or derivative thereof, a glutathione-S-transferasemoiety, a moiety of six or more consecutive histidine residues, an aminoacid sequence or hapten to function as an epitope tag, a fluorochrome,an enzyme or enzyme fragment. The kinase substrate may be linked tothese or other features with a molecular spacer arm to avoid sterichindrance.

In another example the kinase substrate may be labelled with afluorophore. The binding of the reagent to the labelled substrate insolution may be followed by the technique of fluorescence polarizationas it is described in the literature. In a variation of this example, afluorescent tracer molecule may compete with the substrate for theanalyte to detect kinase activity by a technique which is know to thoseskilled in the art as indirect fluorescence polarization.

In yet another example, radioactive gamma-ATP is used in the kinasereaction, and the effect of the test agent on the incorporation ofradioactive phosphate in the test substrate is determined relative tocontrol conditions.

It has been shown that the compounds of the invention exhibit low IC₅₀values in in vitro biological screening assays for inhibition of MNK 1and/or MNK 2 kinase activity. The following table contains the testresults for exemplary compounds.

E. Biological Data

TABLE 1 Biological data of the compounds of the present invention asobtained in assay 2. MNK2 Example IC50 [nM] 1.1 9 1.2 19 1.3 3 1.4 2 1.52 1.6 1 1.7 2 1.8 2 1.9 2 1.10 21 1.11 32 1.12 4 1.13 4 1.14 5 1.15 31.16 2 1.17 2 1.18 2 1.19 4 1.20 2 1.21 7 1.22 1 1.23 5 1.24 3 1.25 21.26 3 1.27 3 1.28 4 1.29 2 1.30 3 1.31 6 1.32 4 1.33 8 1.34 3 1.35 11.36 3 1.37 3 2.1 22 2.2 6 2.3 6 2.4 17 2.5 17 2.6 91 2.7 9 2.8 2 2.9 42.10 2 2.11 14 2.12 3 2.13 16 2.14 108 2.15 78 2.16 82 2.17 21 2.18 492.19 132 2.20 27 2.21 179 2.22 7 2.23 23 2.24 4 2.25 2 2.26 3 2.27 42.28 11 2.29 2 2.30 7 2.31 16 2.32 8 2.33 7 2.34 24 2.35 9 2.36 3 2.37 42.38 3 2.39 7 2.40 6 2.41 2 2.42 4 2.43 3 2.44 4 2.45 7 2.46 4 2.47 32.48 7 2.49 6 2.50 4 2.51 11 2.52 15 2.53 4 2.54 3 2.55 3 2.56 2 2.57 62.58 2 2.59 4 2.60 3 2.61 12 2.62 33 2.63 2 2.64 9 2.65 10 2.66 3 2.67 42.68 11 2.69 22 2.70 10 2.71 6 2.72 10 2.73 20 2.74 7 2.75 8 2.76 7 2.778 2.78 11 2.79 10 2.80 4 2.81 14 2.82 8 2.83 4 2.84 19 2.85 3 2.86 132.87 10 2.88 32 2.89 51 2.90 70 2.91 106 2.92 2 2.93 24 2.94 39 2.95 542.96 9 2.97 71 2.98 6 2.99 3 2.100 25 2.101 6 2.102 31 3.1 29 3.2 47 3.326 3.4 21 3.5 6 3.6 10 3.7 38 4.1 45 4.2 8 4.3 40 4.4 11 4.5 33 5.1 165.2 72 5.3 109 5.4 44 5.5 13 6.1 389 6.2 185 6.3 584 6.4 20 6.5 28 6.680 6.7 62 6.8 128 6.9 7 6.10 378 7.1 45 7.2 6 7.3 7 8.1 3 8.2 3 8.3 68.4 11 8.5 21 9.1 2 9.2 2 9.3 26 9.4 7 9.5 1 9.6 8 9.7 204 9.8 39 9.9 79.10 3 9.11 15 9.12 27 9.13 6 9.14 13 9.15 32 9.16 7 9.17 33 9.18 8 9.1942 9.20 23 9.21 23 9.22 18 9.23 8 9.24 4 9.25 26 9.26 7 9.27 86 9.28 139.29 3 9.30 43 10.1 1 10.2 2 10.3 3 10.4 3 11.1 54 11.2 31 11.3 12 11.459 12.1 3 12.2 3 13.1 6 13.2 13 13.3 15 14.1 1 14.2 10 14.3 19 14.4 214.5 3 14.6 2 14.7 7 14.8 1 14.9 3 14.10 2 14.11 4 14.12 15

TABLE 2 Biological data of selected compounds of the present inventionas obtained in assay 3. MNK1 # IC50 [nM] 1.1 104 1.2 383 1.6 45 1.7 181.9 28 1.15 34 1.27 33 1.35 25 2.12 94 2.18 359 2.25 46 2.26 100 2.29 402.36 51 2.42 39 2.45 92 2.50 61 2.54 66 2.58 55 2.60 37 2.75 95 2.78 1072.92 44 3.5 97 5.1 373 6.6 1400 8.4 104 9.10 28 9.19 329 10.1 55 10.3 4114.8 80

TABLE 3 % Inhibition of MNK1 at a compound concentration of 1 μM asobtained in assay 3 MNK1 Example % INH 1.3 95 1.4 97 1.5 88 1.9 98 1.1164 1.12 88 1.13 100 1.14 96 1.15 103 1.16 96 1.17 103 1.18 97 1.19 991.20 97 1.21 93 1.22 92 1.23 99 1.24 91 1.25 97 1.26 99 1.28 96 1.29 1001.30 93 1.31 91 1.32 94 1.33 96 1.34 97 1.36 98 1.37 97 2.1 88 2.3 1022.4 93 2.5 85 2.6 63 2.7 97 2.8 100 2.10 105 2.11 79 2.13 90 2.14 192.15 31 2.16 55 2.17 18 2.19 45 2.20 77 2.21 57 2.22 86 2.23 75 2.24 992.27 97 2.28 85 2.29 104 2.30 97 2.31 94 2.32 97 2.33 91 2.34 70 2.35 972.37 93 2.38 96 2.39 86 2.40 96 2.43 100 2.45 92 2.46 95 2.47 103 2.4890 2.49 94 2.51 81 2.52 97 2.53 83 2.55 91 2.56 95 2.57 82 2.59 99 2.6278 2.63 102 2.64 88 2.65 100 2.66 100 2.67 100 2.68 94 2.70 92 2.71 942.72 98 2.74 91 2.76 96 2.77 94 2.79 85 2.80 96 2.81 91 2.82 94 2.83 972.85 97 2.92 99 2.102 74 3.1 93 3.2 66 3.3 88 3.4 82 3.6 98 3.7 84 4.164 4.2 87 4.3 54 4.4 93 4.5 63 5.2 56 5.3 31 5.4 35 5.5 85 6.1 10 6.2 316.3 9 6.4 62 6.5 60 6.7 35 6.8 41 6.9 90 6.10 38 7.1 62 7.2 94 7.3 938.1 97 8.2 100 8.3 97 8.5 97 9.1 96 9.2 94 9.3 90 9.4 102 9.6 94 9.7 789.8 75 9.9 94 9.10 104 9.12 86 9.13 99 9.14 84 9.15 82 9.16 98 9.17 929.18 97 9.20 87 9.21 84 9.23 93 9.24 97 9.29 94 10.2 93 10.4 104 11.1 4411.2 75 11.3 87 11.4 56 13.1 96 13.2 69 13.3 79 14.1 97 14.2 86 14.3 10014.4 103 14.5 99 14.6 101 14.9 100 14.10 101 14.11 96 14.12 86Method of Treatment

In view of their ability to inhibit the activity of the MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) kinase, the compounds of generalformula I according to the invention, including the corresponding saltsthereof, are theoretically suitable for the treatment of all thosediseases or conditions which may be affected or which are mediated bythe inhibition of the MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)kinase.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the inhibition of the MNK1 (MNK1a or MNK1b) and/orMNK2 (MNK2a or MNK2b) kinase in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the inhibition of the MNK1(MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase in a mammal thatincludes the step of administering to a patient, preferably a human, inneed of such treatment a therapeutically effective amount of a compoundor a pharmaceutical composition of the present invention.

Diseases and conditions mediated by inhibitors of the inhibition of theMNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase embracemetabolic diseases or conditions.

The present invention is directed to compounds which are useful in thetreatment and/or prevention of a disease, disorder and/or conditionwherein the inhibition of the activity of the MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) kinase is of therapeutic benefit, includingbut not limited to the treatment of metabolic diseases, such as obesity,eating disorders, cachexia, diabetes mellitus, metabolic syndrome,hypertension, coronary heart diseases, hypercholesterolemia,dyslipidemia, osteoarthritis, biliary stones and/or sleep apnea anddiseases related to reactive oxygen compounds (ROS defense) such asdiabetes mellitus, neurodegenerative diseases and cancer.

The pharmaceutical compositions of the invention are particularly usefulfor prophylaxis and treatment of obesity, diabetes mellitus and othermetabolic diseases of the carbohydrate and lipid metabolism as statedabove, in particular diabetes mellitus and obesity.

Thus, in a more preferred embodiment of this invention the use of acompound of the invention for the production of a pharmaceuticalcomposition for the prophylaxis or therapy of metabolic diseases isprovided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing a cytokine mediated disorder such as aninflammatory disease is provided.

The pharmaceutical compositions of the invention are thus useful for theprophylaxis or therapy of inflammatory diseases, in particular chronicor acute inflammation, chronic inflammatory arthritis, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoidarthritis, gouty arthritis; psoriasis, erythrodermic psoriasis, pustularpsoriasis, inflammatory bowel disease, Crohn's disease and relatedconditions, ulcerative colitis, colitis, diverticulitis, nephritis,urethritis, salpingitis, oophoritis, endomyometritis, spondylitis,systemic lupus erythematosus and related disorders, multiple sclerosis,asthma, meningitis, myelitis, encephalomyelitis, encephalitis,phlebitis, thrombophlebitis, chronic obstructive disease (COPD),inflammatory lung disease, allergic rhinitis, endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis,oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, dermatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

As already stated above, the compositions of the present invention areparticularly useful for treating or preventing a disease selected fromchronic or acute inflammation, chronic inflammatory arthritis,rheumatoid arthritis, psoriasis, COPD, inflammatory bowel disease,septic shock, Crohn's disease, ulcerative colitis, multiple sclerosisand asthma.

Thus, in a more preferred embodiment of this invention the use of acompound according to the invention for the production of apharmaceutical composition for the prophylaxis or therapy ofinflammatory diseases selected from chronic or acute inflammation,chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma is provided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing cancer, viral diseases or neurodegenerativediseases is provided.

In a further aspect of the invention the use of a compound of thepresent invention for the production of a pharmaceutical composition forinhibiting the activity of the kinase activity of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a, MNK2b) or further variants thereof is provided, inparticular for the prophylaxis or therapy of metabolic diseases,hematopoietic disorders, cancer and their consecutive complications anddisorders. Whereby the prophylaxis and therapy of metabolic diseases ofthe carbohydrate and/or lipid metabolism is preferred.

For the purpose of the present invention, a therapeutically effectivedosage will generally be from about 1 to 2000 mg/day, preferably fromabout 10 to about 1000 mg/day, and most preferably from about 10 toabout 500 mg/day, which may be administered in one or multiple doses.

It will be appreciated, however, that specific dose level of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

It will be appreciated by the person of ordinary skill in the art thatthe compounds of the invention and the additional therapeutic agent maybe formulated in one single dosage form, or may be present in separatedosage forms and may be either administered concomitantly (i.e. at thesame time) or sequentially.

The pharmaceutical compositions of the present invention may be in anyform suitable for the intended method of administration.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to a person skilled in the arton the basis of his specialist knowledge. The preferred ones are thosethat are suitable for the particular formulation and method ofadministration that are desired. The preparations or formulationsaccording to the invention may be prepared using methods known per sethat are familiar to one skilled in the art, such as for example bymixing or combining at least one compound of formula I according to theinvention, or a pharmaceutically acceptable salt of such a compound andone or more excipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Other active substances which are suitable for such combinationsinclude, for example, antidiabetics like insulin, long and short actinginsulin analogues, sulfonylureas, biguanides, DPP-IV inhibitors, SGLT2inhibitors, 11β-HSD inhibitors, glucokinase activators, AMPK activators,Glp-1 receptor agonists, GIP receptor agonists, DGAT inhibitors,PPARgamma agonists, PPARdelta agonists, and other antidiabetics derivedfrom thiazolidinediones, lipid lowering agents such as statines,fibrates, ion exchange resins nicotinic acid derivatives, or HMG-CoAreductase inhibitors, cardiovascular therapeutics such as nitrates,antihypertensiva such as β-blockers, ACE inhibitors, Ca-channelblockers, angiotensin II receptor antagonists, diuretics, thrombocyteaggregation inhibitors, or antineoplastic agents such as alkaloids,alkylating agents, antibiotics, or antimetabolites, or anti-obesityagents. Further preferred compositions are compositions wherein theadditional therapeutic agent is selected from a histamine antagonist, abradikinin antagonist, serotonin antagonist, leukotriene, ananti-asthmatic, an NSAID, an antipyretic, a corticosteroid, anantibiotic, an analgetic, a uricosuric agent, chemotherapeutic agent, ananti gout agent, a bronchodilator, a cyclooxygenase-2 inhibitor, asteroid, a 5-lipoxygenase inhibitor, an immunosuppressive agent, aleukotriene antagonist, a cytostatic agent, an antineoplastic agent, amTor inhibitor, a Tyrosine kinase inhibitor, antibodies or fragmentsthereof against cytokines and soluble parts (fragments) of cytokinereceptors.

More particularly preferred are compounds such as human NPH insulin,human lente or ultralente insulin, insulin Lispro, insulin Aspart,insulin Glulisine, insulin detemir or insulin Glargine, metformin,phenformin, acarbose, miglitol, voglibose, pioglitazone, rosiglizatone,rivoglitazone, aleglitazar, alogliptin, saxagliptin, sitagliptin,vildagliptin, exenatide, liraglutide, albiglutide, pramlintide,carbutamide, chlorpropamide, glibenclamide (glyburide), gliclazide,glimepiride, glipizide, gliquidone, tolazamide, tolbutamide, atenolol,bisoprolol, metoprolol, esmolol, celiprolol, talinolol, oxprenolol,pindolol, propanolol, bupropanolol, penbutolol, mepindolol, sotalol,certeolol, nadolol, carvedilol, nifedipin, nitrendipin, amlodipin,nicardipin, nisoldipin, diltiazem, enalapril, verapamil, gallopamil,quinapril, captopril, lisinopril, benazepril, ramipril, peridopril,fosinopril, trandolapril, irbesatan, losartan, valsartan, telmisartan,eprosartan, olmesartan, hydrochlorothiazide, piretanid, chlorotalidone,mefruside, furosemide, bendroflumethiazid, triamterene, dehydralazine,acetylsalicylic acid, tirofiban-HCl, dipyramidol, triclopidin,iloprost-trometanol, eptifibatide, clopidogrel, piratecam, abciximab,trapidil, simvastatine, bezafibrate, fenofibrate, gemfibrozil,etofyllin, clofibrate, etofibrate, fluvastatine, lovastatine,pravastatin, colestyramide, colestipol-HCl, xantinol nicotinat, inositolnicotinat, acipimox, nebivolol, glycerolnitrate, isosorbide mononitrate,isosorbide dinitrate, pentaerythrityl tetranitrate, indapamide,cilazepril, urapidil, eprosartan, nilvadipin, metoprolol, doxazosin,molsidormin, moxaverin, acebutolol, prazosine, trapidil, clonidine,vinca alkaloids and analogues such as vinblastin, vincristin, vindesin,vinorelbin, podophyllotoxine derivatives, etoposid, teniposid,alkylating agents, nitroso ureas, N-lost analogues, cycloplonphamid,estamustin, melphalan, ifosfamid, mitoxantron, idarubicin, doxorubicin,bleomycin, mitomycin, dactinomycin, daptomycin, docetaxel, paclitaxel,carboplatin, cisplatin, oxaliplatin, BBR3464, satraplatin, busulfan,treosulfan, procarbazine, dacarbazine, temozolomide, chlorambucil,chlormethine, cyclophosphamide, ifosfamide, melphalan, bendamustine,uramustine, ThioTEPA, camptothecin, topotecan, irinotecan, rubitecan,etoposide, teniposide, cetuximab, panitumumab, trastuzumab, rituximab,tositumomab, alemtuzumab, bevacizumab, gemtuzumab, aminolevulinic acid,methyl aminolevulinate, porfimer sodium, verteporfin, axitinib,bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib,vandetanib, retinoids (alitretinoin, tretinoin), altretamine, amsacrine,anagrelide, arsenic trioxide, asparaginase (pegaspargase), bexarotene,bortezomib, denileukin diftitox, estramustine, ixabepilone, masoprocol,mitotane, testolactone, tipifarnib, abetimus, deforolimus, everolimus,gusperimus, pimecrolimus, sirolimus, tacrolimus, temsirolimus,antimetabolites such as cytarabin, fluorouracil, fluoroarabin,gemcitabin, tioguanin, capecitabin, combinations such asadriamycin/daunorubicin, cytosine arabinosid/cytarabine, 4-HC, or otherphosphamides.

Other particularly preferred compounds are compounds such as clemastine,diphenhydramine, dimenhydrinate, promethazine, cetirizine, astemizole,levocabastine, loratidine, terfenadine, acetylsalicylic acid, sodoumsalicylate, salsalate, diflunisal, salicylsalicylic acid, mesalazine,sulfasalazine, osalazine, acetaminophen, indomethacin, sulindac,etodolac, tolmetin, ketorolac, bethamethason, budesonide, chromoglycinicacid, dimeticone, simeticone, domperidone, metoclopramid, acemetacine,oxaceprol, ibuprofen, naproxen, ketoprofen, flubriprofen, fenoprofen,oxaprozin, mefenamic acid, meclofenamic acid, pheylbutazone,oxyphenbutazone, azapropazone, nimesulide, metamizole, leflunamide,eforicoxib, lonazolac, misoprostol, paracetamol, aceclofenac,valdecoxib, parecoxib, celecoxib, propyphenazon, codein, oxapozin,dapson, prednisone, prednisolon, triamcinolone, dexibuprofen,dexamethasone, flunisolide, albuterol, salmeterol, terbutalin,theophylline, caffeine, naproxen, glucosamine sulfate, etanercept,ketoprofen, adalimumab, hyaluronic acid, indometacine, proglumetacinedimaleate, hydroxychloroquine, chloroquine, infliximab, etofenamate,auranofin, gold, [²²⁴Ra]radium chloride, tiaprofenic acid,dexketoprofen(trometamol), cloprednol, sodium aurothiomalateaurothioglucose, colchicine, allopurinol, probenecid, sulfinpyrazone,benzbromarone, carbamazepine, lornoxicam, fluorcortolon, diclofenac,efalizumab, idarubicin, doxorubicin, bleomycin, mitomycin, dactinomycin,daptomycin, cytarabin, fluorouracil, fluoroarabin, gemcitabin,tioguanin, capecitabin, adriamydin/daunorubicin, cytosinearabinosid/cytarabine, 4-HC, or other phosphamides, penicillamine, ahyaluronic acid preparation, arteparon, glucosamine, MTX, solublefragments of the TNF-receptor (such as etanercept (Enbrel)) andantibodies against TNF (such as infliximab (Remicade), natalizumab(Tysabri) and adalimumab (Humira)).

EXAMPLES

Preliminary Remarks:

The hereinafter described compounds have been characterized throughtheir characteristic mass after ionisation in a mass-spectrometer, theirRf-value on thin-layer-chromatography plate and/or their retention timeon an analytical HPLC.

Unless stated otherwise, bold wedges and hash wedges indicate absolutestereochemistry of pure stereoisomers. The signifier “rac.” indicatesthat the structure is a racemic mixture rather than a pure stereoisomer.

List of Abbreviations

ACN Acetonitrile

AcOH Acetic acid

aq. Aqueous

BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl

BOC tert-butoxy-carbonyl-

° C. degree Celsius

CH Cyclohexane

DA diode array

dba Dibenzylideneacetone

DCM Dichloromethane

DMF N,N-dimethylformamide

Eq. Molar equivalent(s)

ESI-MS electrospray ionisation mass spectrometry

EtOAc ethyl acetate

EtOH Ethanol

FC Flash-chromatography, SiO₂ is used if no further details given

h Hour

HPLC high performance liquid chromatography

RP-HPLC Reversed Phase HPLC

L Liter

LiHMDS Lithium Hexamethyldisilazide

m/z Mass-to-charge ratio

MeOH Methanol

min Minute

ml Milliliter

MS mass spectrum

IW Reaction was performed in a microwave

n.d. not determined

NH₄OH solution of NH₃ in water

psi pound per square inch

pTsOH p-Toluenesulfonic acid

Rac. racemic

RT room temperature (about 20° C.)

R_(t) retention time

Sol Solvent

TF/TFA trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

HPLC Methods

HPLC-A:

Agilent 1200 with DA- and MS-detector, XBridge C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-B:

Agilent 1200 with DA- and MS-Detector, Sunfire C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-D:

Waters 1525 with DA- and MS-detector, Sunfire C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 4.0 0.15 97.0 3.0 3.0 2.15 0.0 100.0 3.0 2.2 0.0 100.0 4.5 2.40.0 100.0 4.5HPLC-E:

Agilent 1200 with DA- and MS-detector, StableBond C18_3.0×30 mm, 1.8 μm(Agilent), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-F:

Waters 1525 with DA- and MS-detector, XBridge C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 4.0 0.15 97.0 3.0 3.0 2.15 0.0 100.0 3.0 2.2 0.0 100.0 4.5 2.40.0 100.0 4.5HPLC-H:

Agilent 1200 with DA- and MS-detector, XBridge C18_3×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Methanol] [ml/min] 0.0 95.05.0 2.2 0.3 95.0 5.0 2.2 1.5 0.0 100.0 2.2 1.55 0.0 100.0 2.9 1.65 0.0100.0 2.9HPLC-J:

Agilent 1100 with DAD, Gilson autosampler and MS-detector, SunFireC18_4.6×30 mm, 3.5 μm (Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Acetonitrile] [ml/min] 0.098.0 2.0 2.5 1.5 0.0 100.0 2.5 1.8 0.0 100.0 2.5HPLC-K:

Waters Acquity with 3100 MS, XBridge BEH C18_3.0×30 mm, 1.7 μm (Waters),60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% NH₄OH] [Acetonitrile] [ml/min] 0.095.0 5.0 1.5 0.7 0.1 99.9 1.5 0.8 0.1 99.9 1.5 0.81 95.0 5.0 1.5 1.195.0 5.0 1.5HPLC-M:

Agilent 1200 with DA- and MS-detector, XBridge C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% NH₄OH] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-N:

Waters Acquity with DA- and MS-detector and CTC autosampler, XBridgeC18_3.0×30 mm, 2.5 μm (Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% NH₄OH] [Acetonitrile] [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0HPLC-P:

Agilent 1100 with DAD, CTC autosampler and Waters MS-detector, XBridgeC18_4.6×30 mm, 3.5 μm (Waters), 60° C.

Tim % Sol % Sol Flow [min] [H₂O 0.1% NH₄OH] [Acetonitrile] [ml/min] 0.098.0 2.0 2.5 1.5 0.0 100.0 2.5 1.8 0.0 100.0 2.5HPLC-S:

Waters 1525 with DA- and MS-detector, XBridge C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol % Sol Flow [min] [H₂O 0.1% TFA] [Methanol] [ml/min] 0.0 95.05.0 4.0 0.05 95.0 5.0 3.0 2.05 0.0 100.0 3.0 2.1 0.0 100.0 4.5 2.4 0.0100.0 4.5HPLC-V:

Agilent 1100 with DA-detector, XBridge C18_3.0×30 mm, 2.5 μm (Waters),60° C.

Gradient/Solvent % Sol % Sol Flow Time [min] [H2O 0.1% NH4OH][Acetonitrile] [ml/min] 0.0 98.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.02.0HPLC-W:

XBridge BEH C18_2.1×30 mm, 1.7 μm (Waters), 60° C.

Gradient/Solvent % Sol % Sol Flow Time [min] [H2O, 0.1% TFA][Acetonitril] [ml/min] 0.0 99 1 1.6 0.02 99 1 1.6 1.00 0 100 1.6 1.10 0100 1.6HPLC-X:

Sunfire C18_3.0×30 mm, 2.5 μm (Waters), 60° C.

Gradient/Solvent % Sol % Sol Flow Time [min] [H2O 0.1% TFA][Acetonitrile] [ml/min] 0.0 98.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.02.0HPLC-AA:

Sunfire C18, 2.1×30 mm, 2.5 μm (Waters), 60° C.

Gradient/Solvent % Sol % Sol Flow Time [min] [H2O, 0.1% TFA][Acetonitril] [ml/min] 0.0 99 1 1.5 0.02 99 1 1.5 1.00 0 100 1.5 1.10 0100 1.5

Preparation of Intermediates Intermediate I.1:2-amino-4-bromo-6-fluoro-benzonitrile

5.0 g (22.9 mmol) 4-bromo-2,6-difluorobenzonitrile in 200 ml of asolution of NH₃ in ethanol are heated in a pressure vessel to 90° C. for20 h. After cooling to RT the solvent is evaporated and the residuetaken up in water/DCM. The organic phase is separated, dried andevaporated.

Yield: 4.9 g (99%), ESI-MS: m/z=213/215 (M−H)⁻, R_(t)(HPLC): 1.72 min(HPLC-S)

Intermediate II.1:N′-(5-bromo-2-cyano-3-fluoro-phenyl)-N,N-dimethyl-formamidine

17.0 g (79.1 mmol) 2-amino-4-bromo-6-fluoro-benzonitrile in 140 ml ofN,N-dimethylformamide dimethyl acetal are heated to 120° C. for 2 h.After cooling RT the solvent is evaporated and the residue taken up indiethyl ether, filtered and dried.

Yield: 20.5 g (96%), ESI-MS: m/z=270/272 (M+H)⁺, R_(t)(HPLC): 0.83 min(HPLC-H)

The following intermediates are prepared in a similar manner asintermediate II.1 from the corresponding anilines which are commerciallyavailable or can be obtained according to (a) U.S. Pat. No. 3,987,192and (b) J. Med. Chem. 1981, 24 (6), 742.

ESI-MS HPLC m/z R_(t) Name Structure Starting Material M + H⁺ MethodII.1A

2-amino-4-bromo-6- methyl-benzonitrile^((a)) 266/268 0.57 min HPLC-AII.1B

2-amino-6-chloro- benzonitrile^((b)) 208 0.47 min HPLC-A II.1C

2-amino-6-bromo- benzonitrile^((b)) 252/254 0.53 min HPLC-A II.1D

2-amino-6- difluoromethoxy- benzonitrile (Intermediate IV.2AA) 240 0.63HPLC- HPLC-E II.1E

Intermediate V.14 206 0.92 min HPLC M

Intermediate II.2:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-methyl-phenyl]-N,N-dimethyl-formamidine

To 0.5 g (1.9 mmol) intermediate II.1A in 20 ml dioxane 0.2 g (2.3 mmol)dimethylsulphoximine (V.1), 0.1 g (0.4 mmol) 2-(di-t-butylphosphino)biphenyl, 0.1 g (0.14 mmol) Pd₂dba₃ and 0.3 g (2.7 mmol) sodiumtert-butoxide are added and the mixture is heated to 80° C. for 1 h. Thereaction mixture is diluted with water, acidified with citric acid andextracted with EtOAc, then alkalified and extracted with DCM. Theorganic phases are pooled, dried and evaporated.

Yield: 0.4 g (83%), ESI-MS: m/z=279 (M+H)⁺, R_(t)(HPLC): 0.59 min(HPLC-H)

The following intermediates II.2A through II.2E are prepared in asimilar manner as intermediate II.2:

Intermediate II.2A:N′-[2-Cyano-3-methyl-5-(1-oxo-tetrahydro-1λ⁶-thiophen-1-ylideneamino)-phenyl]-N,N-dimethyl-formamidine

Synthesis from intermediate II.1A and intermediate V.5.

ESI-MS: m/z=305 (M+H)⁺, R_(t)(HPLC): 0.63 min (HPLC-B)

Intermediate II.2B:N′-[2-Cyano-3-fluoro-5-(1-oxo-tetrahydro-1λ⁶-thiophen-1-ylideneamino)-phenyl]-N,N-dimethyl-formamidine

Synthesis from intermediates II.1 and V.5.

ESI-MS: m/z=309 (M+H)⁺, R_(t)(HPLC): 0.64 min (HPLC-B)

Intermediate II.2C:N′-[3-flouro-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Synthesis from intermediates II.1 and V.1.

ESI-MS: m/z=283 (M+H)⁺, R_(t)(HPLC): 0.58 min (HPLC-B)

Intermediate II.2D:N′-[3-Fluoro-2-cyano-5-(1-oxo-1λ⁶-thietan-1-ylideneamino)-phenyl]-N,N-dimethyl-formamidine

Synthesis from intermediates II.1 and V.4.

ESI-MS: m/z=295 (M+H)⁺

Intermediate II.2E:N′-[3-Methyl-2-cyano-5-(1-oxo-1λ⁶-thietan-1-ylideneamino)-phenyl]-N,N-dimethyl-formamidine

Synthesis from intermediates II.1A and V.4.

ESI-MS: m/z=291 (M+H)⁺, R_(t)(HPLC): 0.63 min (HPLC-E)

Intermediate II.3:N′-[3-chloro-2-cyano-5-[[dimethyl(oxo)-λ⁶⁻sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

0.2 g (0.96 mmol) intermediate II.1B, 0.2 g (0.67 mmol)bis(pinacolato)diborane, 26 mg (0.01 mmol)4,4′-di-tert-butyl-[2,2′]bipyridinyl and 40 mg (0.06 mmol)chloro(1,5-cyclooctadiene)iridium(I) dimer are heated in heptane atreflux for 2 days. After cooling to RT the solvent is evaporated and theresidue taken up in water/EtOAc. The organic phase is separated, driedand evaporated yielding the crude corresponding boronic acid derivativewhich is dissolved in MeOH. 0.1 g (0.75 mmol) dimethylsulfoximine (V.1)and 14 mg (0.08 mmol) copper(II) acetate are added and the reactionmixture is stirred at RT over night. After addition of MeOH andconcentrated aqueous NH₃ solution, the solvent is evaporated and theresidue purified by FC.

Yield: 0.1 g (58%), ESI-MS: m/z=299 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-M)

The following intermediates II.3A through II.3G are prepared in asimilar manner as intermediate II.3:

Intermediate II.3A:N′-[3-chloro-2-cyano-5-[(1-oxothiolan-1-ylidene)amino]phenyl]-N,N-dimethyl-formamidine

Prepared from intermediates II.1B and V.5.

ESI-MS: m/z=325/327 (M+H)⁺, R_(t)(HPLC): 0.75 min (HPLC-M)

Intermediate II.3B:N′-[3-Chloro-2-cyano-5-(1-oxo-1λ⁶-thietan-1-ylideneamino)-phenyl]-N,N-dimethyl-formamidine

Prepared from intermediates II.1B and V.4.

ESI-MS: m/z=311/313 (M+H)⁺, R_(t)(HPLC): 0.55 min (HPLC-A)

Intermediate II.3C:N′-[3-bromo-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Prepared in from intermediates II.1C and V.1.

ESI-MS: m/z=343/345 (M+H)⁺, R_(t)(HPLC): 0.66 min (HPLC-E)

Intermediate II.3D:N′-[3-difluoromethoxy-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Prepared from intermediates II.1D and V.1.

ESI-MS: m/z=331 (M+H)⁺, R_(t)(HPLC): 1.01 min (HPLC-E)

Intermediate II.3E:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-formamidine

prepared from 2-amino-6-(trifluoromethyl)benzonitrile and intermediateV.1.

ESI-MS: m/z=333 (M+H)⁺, R_(t)(HPLC): 0.71 min (HPLC-E)

Intermediate II.3F:N′-[3-trifluoromethyl-2-cyano-5-[(1-oxothiolan-1-ylidene)amino]phenyl]-N,N-dimethyl-formamidine

prepared from 2-amino-6-(trifluoromethyl)benzonitrile and intermediateV.5.

ESI-MS: m/z=359 (M+H)⁺, R_(t)(HPLC): 0.77 min (HPLC-E)

Intermediate II.3G:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-4-fluoro-3-methyl-phenyl]-N,N-dimethyl-formamidine

prepared from intermediate II.1E and intermediate V.1.

ESI-MS: m/z=297 (M+H)⁺, R_(t)(HPLC): 0.77 min (HPLC-M)

Intermediate I.4:N′-[2-cyano-3-cyclopropyl-5-[[dimethyl(oxo-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

To a solution of 100 mg (0.29 mmol) intermediate II.3C in 20 ml dioxane25 mg (0.29 mmol) cyclopropylboronic acid, 0.1 g (0.4 mmol)1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II), 121 mg (2.7mmol) potassium carbonate are added and the mixture heated to 80° C.over night. The reaction mixture is cooled to RT and diluted with MeOHand evaporated. The residue is purified by HPLC.

Yield: 70 mg (79%), ESI-MS: m/z=305 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-A)

Intermediate III.1:(3S,4S)-tert-Butyl-[4-(5-fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-yloxy]-dimethyl-silane

A mixture of 2,4-difluoronitrobenzene (2.81 ml; 25.7 mmol),(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.3, 7.00 g; 25.6 mmol THF (100 ml), and sodium hydride(60% dispersion in mineral oil; 1.03 g; 25.7 mmol) is stirred at RT overnight. DCM is added and the mixture is extracted with water. The organiclayer is separated, dried with magnesium sulphate, filtered andevaporated. The residue is purified by FC (DCM).

Yield: 6.07 g (66%), ESI-MS: m/z=358 (M+H)⁺

The following intermediates III.1A through III.1Q are prepared in asimilar manner to intermediate III.1:

Intermediate III.1A:rac-cis-3-(5-Fluoro-2-nitro-phenoxy)-4-methoxy-tetrahydrofuran

Synthesis from 2,4-difluoronitrobenzene andrac-cis-3-hydroxy-4-methoxy-tetrahydrofuran (intermediate VII.1).

ESI-MS: m/z=258 (M+H)⁺

Intermediate III.1B:rac-trans-2-(4-Methoxy-tetrahydro-furan-3-yloxy)-3-nitro-pyridine

Synthesis from 2-fluoro-3-nitropyridine andrac-trans-3-hydroxy-4-methoxy-tetrahydrofuran (intermediate VII.2)applying lithium bis(trimethylsilyl)amide as base.

ESI-MS: m/z=241 (M+H)⁺

Intermediate III.1C:rac-cis-4-(3-Nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol

Synthesis from 2-chloro-3-nitropyridine and 1,4-anhydroerythritol.

ESI-MS: m/z=227 (M+H)⁺

Intermediate II.1D:rac-cis-4-(5-Fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-ol

Synthesis from 2,4-difluoronitrobenzene and 1,4-anhydroerythritol (2eq.) applying DMF as solvent.

ESI-MS: m/z=244 (M+H)⁺

Intermediate III.1E:rac-trans-4-(5-Fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-carbonitrile

Synthesis from 2,4-difluoronitrobenzene andrac-trans-3-cyano-4-hydroxy-tetrahydrofuran (intermediate VII.6).

ESI-MS: m/z=244 (M+H)⁺

Intermediate III.1F:(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

Synthesis from 2,4-difluoronitrobenzene and(3R,4R)-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate VII.7).

ESI-MS: m/z=457 (M+H)⁺

Intermediate III.1G:(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

Synthesis from 2,4-difluoronitrobenzene and(3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate VII.8).

ESI-MS: m/z=457 (M+H)⁺

Intermediate III.1H:(3S,4S)-1-Benzyl-3-(tert-butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine

Synthesis from 2,4-difluoronitrobenzene and(3S,4S)-1-benzyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-3-ol(intermediate VII.9) applying potassium tert-butylate as base.

ESI-MS: m/z=447 (M+H)⁺

Intermediate III.1I:(3R,4R)-3-(5-Fluoro-2-nitro-phenoxy)-4-methoxy-pyrrolidine-1-carboxylicacid benzyl ester

Synthesis from 2,4-difluoronitrobenzene and(3R,4R)-3-hydroxy-4-methoxy-pyrrolidine-1-carboxylic acid benzyl ester(intermediate VII.10) applying lithium bis(trimethylsilyl)amide as base.

ESI-MS: m/z=391 (M+H)⁺

Intermediate III.1K:(3R,4R)-3-Methoxy-4-(3-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylicacid benzyl ester

Synthesis from 2-fluoro-3-nitropyridine and(3R,4R)-3-hydroxy-4-methoxy-pyrrolidine-1-carboxylic acid benzyl ester(intermediate VII.10) applying lithium bis(trimethylsilyl)amide as base.

ESI-MS: m/z=374 (M+H)⁺

Intermediate III.1L:(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(3-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

Synthesis from 2-chloro-3-nitropyridine and(3R,4R)-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate VII.7).

ESI-MS: m/z=440 (M+H)⁺

Intermediate III.1 M:(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(3-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

Synthesis from 2-chloro-3-nitropyridine and(3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate VII.8).

ESI-MS: m/z=440 (M+H)⁺

Intermediate III.1N:rac-cis-2-(4-Methoxy-tetrahydro-furan-3-yloxy)-3-nitro-pyridine

Synthesis from 2-chloro-3-nitropyridine andrac-cis-3-hydroxy-4-methoxy-tetrahydrofuran (intermediate VII.1)applying powdered NaOH as base and toluene as solvent. IntermediateVII.1 and the base in toluene are stirred at 0° C., then thechlororarene is added. The mixture is stirred at 50° C. over night.

Intermediate III.1O:exo-6-(5-fluoro-2-nitro-phenoxy)-2-oxabicyclo[2.2.1.]heptane

Synthesis from 2,4-difluoronitrobenzene andexo-2-oxabicyclo[2.2.1.]heptan-6-ol (intermediate VII.12). Reagents aremixed at −5° C., then further reacted at RT.

ESI-MS: m/z=276 (M+Na)⁺

Intermediate III.1P:endo-2-(5-fluoro-2-nitrophenoxy)-7-oxabicyclo[2.2.1]heptane

Synthesis from 2,4-difluoronitrobenzene andendo-7-oxabicyclo[2.2.1]heptan-2-ol (intermediate VII.13). Reagents aremixed at −5° C., then further reacted at RT.

ESI-MS: m/z=254 (M+H)⁺

Intermediate III.1Q:rac-trans-3-fluoro-4-(5-fluoro-2-nitro-phenoxy)-tetrahydro-furan

Synthesis from 2,4-difluoronitrobenzene andrac-trans-4-fluoro-3-hydroxy-tetrahydrofuran (intermediate VIII.1)applying lithium bis(trimethylsilyl)amide as base.

ESI-MS: m/z=245 (M*)+

Intermediate III.2:(3S,4S)-4-(5-Fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-ol

A mixture of(3S,4S)-tert-Butyl-[4-(5-fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-yloxy]-dimethyl-silane(Intermediate III.1, 6.07 g; 12.7 mmol) and AcOH/water/THF (3:1:1, 50ml) is stirred at RT over night. Volatiles are evaporated, the residueis taken up in water and extracted with DCM. The organic layer isseparated, dried with magnesium sulphate, filtered and evaporated. Theresidue is purified by FC (DCM/MeOH 96:4).

Yield: 2.95 g (95%), ESI-MS: m/z=244 (M+H)⁺, Specific rotation: [α]_(D)²⁰ (MeOH)=+21°

The following intermediates III.2A through III.2L are prepared in asimilar manner to intermediate III.2:

Intermediate III.2A:(3R,4R)-4-(5-Fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-ol

Two step procedure starting from 2,4-difluoronitrobenzene and(3R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.4).

ESI-MS: m/z=244 (M+H)⁺, Specific rotation: [α]_(D) ²⁰ (MeOH)=−18°

Intermediate III.2B:(3S,4S)-4-(5-Chloro-2-nitro-phenoxy)-tetrahydro-furan-3-ol

Two step procedure starting from 4-chloro-2-fluoronitrobenzene and(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.3).

ESI-MS: m/z=260 (M+H)⁺

Intermediate III.2C:(3R,4R)-4-(5-Chloro-2-nitro-phenoxy)-tetrahydro-furan-3-ol

Two step procedure starting from 4-chloro-2-fluoronitrobenzene and(3R,4R)-4-(tert-butyl-di methyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.4).

ESI-MS: m/z=260 (M+H)⁺

Intermediate III.2D:(3S,4S)-4-(3-Nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol

Two step procedure starting from 2-Fluoro-3-nitropyridine and(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.3) applying lithium bis(trimethylsilyl)amide as basein the first step.

ESI-MS: m/z=227 (M+H)⁺, Specific rotation: [α]_(D) ²⁰ (MeOH)=+53°

Intermediate III.2E:(3R,4R)-4-(3-Nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol

Two step procedure starting from 2-Fluoro-3-nitropyridine and(3R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.4) applying lithium bis(trimethylsilyl)amide as basein the first step.

ESI-MS: m/z=227 (M+H)⁺, Specific rotation: [α]_(D) ²⁰ (MeOH)=−52°

Intermediate III.2F:(3S,4S)-4-(6-Chloro-3-nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol

Two step procedure starting from 2,6-dichloro-3-nitropyridine and(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.3).

ESI-MS: m/z=261 (M+H)⁺

Intermediate III.2G:(3R,4R)-4-(6-Chloro-3-nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol

Two step procedure starting from 2,6-dichloro-3-nitropyridine and(3R,4R)-4-(tert-butyl-di methyl-silanyloxy)-tetrahydro-furan-3-ol(Intermediate VII.4).

ESI-MS: m/z=261 (M+H)⁺

Intermediate III.2H:(3R,4R)-4-(5-Fluoro-2-nitro-phenoxy)-1-methanesulfonyl-pyrrolidin-3-ol

Prepared from(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-1-methanesulfonyl-pyrrolidine(intermediate III.11).

ESI-MS: m/z=321 (M+H)⁺

Intermediate III.2I:(3R,4R)-1-[3-Hydroxy-4-(3-nitro-pyridin-2-yloxy)-pyrrolidin-1-yl]-ethanone

Prepared from(3R,4R)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-4-(3-nitro-pyridin-2-yloxy)-pyrrolidin-1-yl]-ethanone(intermediate III.9B); reaction at 80° C.

ESI-MS: m/z=268 (M+H)⁺

Intermediate III.2K:(3R,4R)-1-Methanesulfonyl-4-(3-nitro-pyridin-2-yloxy)-pyrrolidin-3-ol

Prepared from(3R,4R)-2-[4-(tert-butyl-dimethyl-silanyloxy)-1-methanesulfonyl-pyrrolidin-3-yloxy]-3-nitro-pyridine(intermediate III.11A).

ESI-MS: m/z=304 (M+H)⁺

Intermediate III.2L:(3S,4S)-4-(5-Fluoro-2-nitro-phenoxy)-1-methanesulfonyl-pyrrolidin-3-ol

Prepared from(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-1-methanesulfonyl-pyrrolidine(intermediate III.11B).

ESI-MS: m/z=321 (M+H)⁺

Intermediate III.3:rac-cis-2-[4-(2-Fluoro-ethoxy)-tetrahydro-furan-3-yloxy]-3-nitro-pyridine

To a solution ofrac-cis-4-(3-Nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol (intermediateIII.1C, 3.80 g; 16.8 mmol)) in DMF (40 ml) is added sodium hydride (55%in mineral oil; 0.73 g; 16.8 mmol). The mixture is stirred for 5 min,then 1-bromo-2-fluoroethane (1.87 ml; 25.2 mmol) is added. The mixtureis stirred at RT over night, then additional same quantities of sodiumhydride and 1-bromo-2-fluoroethane are added. The mixture is stirred forfurther 6 h at RT, then volatiles are evaporated, the residue is takenup in EtOAc and washed with water. The organic layer is separated, driedwith magnesium sulphate, filtered and evaporated. The residue ispurified by FC (CH/EtOAc 20→60%).

Yield: 1.11 g (18%), ESI-MS: m/z=273 (M+H)⁺

Intermediate III.4:rac-trans-3-(5-Fluoro-2-nitro-phenoxy)-6-methoxy-3,6-dihydro-2H-pyran

A mixture of 2-nitro-5-fluorophenol (0.20 g; 1.27 mmol),rac-cis-6-methoxy-3,6-dihydro-2H-pyran-3-ol (intermediate VII.5; 0.215g; 1.66 mmol), di-tert-butyl azodicarboxylate (0.44 g; 1.91 mmol) andtriphenylphosphine (0.50 g; 1.91 mmol) in THF (5.0 ml) is stirred at RTover night. Volatiles are evaporated and the residue is purified firstby FC (cyclohexane/EtOAc), then by RP-HPLC.

Yield: 170 mg (50%), ESI-MS: m/z=287 (M+NH₄), R_(t)(HPLC): 0.62 min(HPLC-AA)

Intermediate III.5: (3R,4R)-4-(5-Fluoro-2-nitro-phenoxy)-pyrrolidin-3-olhydrochloride

To a mixture of(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate III.1F, 3.01 g; 6.59 mmol) andchlorotrimethylsilane (0.55 ml; 4.35 mmol) in DCM (10 ml) are added afew drops of water. The mixture is stirred over night, evaporated, takenup in dilute NH₄OH and evaporated again. The residue is taken up inmethanol and stirred at RT. The precipitate is filtered off and dried.

Yield: 1.52 g (83%), ESI-MS: m/z=243 (M+H)⁺

Intermediate III.6: (3S,4S)-4-(5-Fluoro-2-nitro-phenoxy)-pyrrolidin-3-ol

To(3S,4S)-1-Benzyl-3-(tert-butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine(intermediate III.1H, 0.79 g; 1.77 mmol in DCM (5.0 ml) is added at 0°C. 1-chloroethyl chloroformate (0.25 ml; 2.34 mmol). The mixture isstirred over night at RT. Methanol (5.0 ml) is added and the mixture isstirred under Argon at 50° C. for 1 h. The mixture is evaporated and theresidue is purified by RP-HPLC (modifier: NH₄OH).

Yield: 300 mg (70%), ESI-MS: m/z=243 (M+H)⁺

Intermediate III.7:(3R,4R)-4-(5-Fluoro-2-nitro-phenoxy)-1-methyl-pyrrolidin-3-ol

A mixture of (3R,4R)-4-(5-Fluoro-2-nitro-phenoxy)-pyrrolidin-3-olhydrochloride (Intermediate III.5, 1.52 g; 5.46 mmol), formaldehyde (37%in water; 0.98 ml; 32.7 mmol) and formic acid (3.09 ml; 82 mmol) isrefluxed over night. The mixture is cooled to RT, diluted with water,alkalified by addition of sodium carbonate solution and extracted withDCM. The organic layer is dried with magnesium sulphate, filtered andevaporated. The residue is purified by FC (DCM/methanol 90:10).

Yield: 1.13 g (81%), ESI-MS: m/z=257 (M+H)⁺

The following intermediates III.7A through III.7B are prepared in asimilar manner to intermediate III.7:

Intermediate III.7A:(3S,4S)-4-(5-Fluoro-2-nitro-phenoxy)-1-methyl-pyrrolidin-3-ol

Prepared from (3S,4S)-4-(5-Fluoro-2-nitro-phenoxy)-pyrrolidin-3-ol(intermediate III.6).

ESI-MS: m/z=257 (M+H)⁺

Intermediate III.7B:(3R,4R)-1-Methyl-4-(3-nitro-pyridin-2-yloxy)-pyrrolidin-3-ol

Prepared from (3R,4R)-4-(3-Nitro-pyridin-2-yloxy)-pyrrolidin-3-ol(intermediate III.12A).

ESI-MS: m/z=240 (M+H)⁺

Intermediate III.8:(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine

A mixture of(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate III.1F, 2.00 g; 4.38 mmol), TFA(0.25 ml, 3.29 mmol) and DCM (10 ml) is stirred over night at RT. Themixture is evaporated and the residue is purified by FC (DCM/methanol0→5%).

Yield: 1.43 g (69%), ESI-MS: m/z=357 (M+H)⁺

The following intermediate III.8A is prepared in a similar manner tointermediate III.8:

Intermediate III.8A:(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine

Prepared from(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate III.1G).

ESI-MS: m/z=357 (M+H)⁺

Intermediate III.9:(3R,4R)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidin-1-yl]-ethanone

To a mixture of(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine(intermediate III.8, 0.88 g; 1.87 mmol), triethylamine (0.58 ml; 4.12mmol) and DCM (5.0 ml) is added acetyl chloride (0.16 ml; 2.25 mmol).The mixture is stirred at RT for 3 days, then water is added, theorganic layer is separated, dried with magnesium sulphate, filtered andevaporated.

Yield: 0.70 g (94%), ESI-MS: m/z=399 (M+H)⁺

The following intermediates III.9A through III.9B are prepared in asimilar manner to intermediate III.9:

Intermediate III.9A:(3S,4S)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidin-1-yl]-ethanone

Prepared from(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine(intermediate III.8A).

ESI-MS: m/z=399 (M+H)⁺

Intermediate III.9B:(3R,4R)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-4-(3-nitro-pyridin-2-yloxy)-pyrrolidin-1-yl]-ethanone

Prepared from(3R,4R)-2-[4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidin-3-yloxy]-3-nitro-pyridineTFA salt (intermediate III.12).

ESI-MS: m/z=382 (M+H)⁺

Intermediate III.1O:(3R,4R)-1-[3-(5-Fluoro-2-nitro-phenoxy)-4-hydroxy-pyrrolidin-1-yl]-ethanone

A mixture of(3R,4R)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidin-1-yl]-ethanone(intermediate III.9, 0.70 g; 1.16 mmol), acetic acid (6.0 ml), TFH (2.0ml) and water (2.0 ml) is stirred at 80° C. for 1 h. Volatiles areevaporated, the residue is taken up in water and alkalified by additionof a small amount of NH₄OH. The precipitate is filtered off with suctionand dried in vacuo at 50° C.

Yield: 0.325 g (65%), ESI-MS: m/z=285 (M+H)⁺

The following intermediate III.10A is prepared in a similar manner tointermediate III.10:

Intermediate III.10A:(3S,4S)-1-[3-(5-Fluoro-2-nitro-phenoxy)-4-hydroxy-pyrrolidin-1-yl]-ethanone

Prepared from(3S,4S)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidin-1-yl]-ethanone(intermediate III.9A).

ESI-MS: m/z=285 (M+H)⁺

Intermediate III.11:(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-1-methanesulfonyl-pyrrolidine

To a mixture of(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidineTFA-salt (intermediate III.8, 1.43 g; 3.04 mmol), triethylamine (0.94ml; 6.69 mmol) and DCM (5.0 ml) is added methanesulphonyl chloride (0.26ml; 3.34 mmol). The mixture is stirred at RT for 3 days, then extractedby addition of water. The organic layer is dried with magnesiumsulphate, filtered and evaporated. The residue is purified by FC(DCM/methanol 0→5%).

Yield: 1.08 g (82%), ESI-MS: m/z=435 (M+H)⁺

The following intermediates III.11A through III.11B are prepared in asimilar manner to intermediate III.11:

Intermediate III.11A:(3R,4R)-2-[4-(tert-Butyl-dimethyl-silanyloxy)-1-methanesulfonyl-pyrrolidin-3-yloxy]-3-nitro-pyridine

Prepared from(3R,4R)-2-[4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidin-3-yloxy]-3-nitro-pyridineTFA salt (intermediate III.12).

ESI-MS: m/z=418 (M+H)⁺

Intermediate III.11B:(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-1-methanesulfonyl-pyrrolidine

Prepared from(3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(5-fluoro-2-nitro-phenoxy)-pyrrolidine(intermediate III.8A).

ESI-MS: m/z=435 (M+H)⁺

Intermediate III.12:(3R,4R)-2-[4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidin-3-yloxy]-3-nitro-pyridineTFA salt

A mixture of(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(3-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate III.1L, 8.90 g; 20.2 mmol), TFA(1.56 ml; 20.2 mmol) and DCM (100 ml) is stirred at RT over night, thenevaporated. The residue is purified by FC (DCM/methanol 0→10%).

Yield: 6.15 g (62%), ESI-MS: m/z=435 (M+H)⁺

The following intermediate III.12A is prepared in a similar manner tointermediate III.12: Intermediate III.12A:(3R,4R)-4-(3-Nitro-pyridin-2-yloxy)-pyrrolidin-3-ol

Prepared from(3R,4R)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(3-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (intermediate III.1L). The compound is isolated asa byproduct of the reaction to intermediate III.12.

Yield: 15%, ESI-MS: m/z=226 (M+H)⁺

Intermediate IV.1:(3S,4S)-4-(3-Amino-6-chloro-pyridin-2-yloxy)-tetrahydro-furan-3-ol

Raney-Nickel (70 mg) is added to the nitroarene starting material(3S,4S)-4-(6-chloro-3-nitro-pyridin-2-yloxy)-tetrahydro-furan-3-ol(intermediate III.2F, 0.67 g; 2.57 mmol) in EtOAc (10 ml). The reactionmixture is stirred at RT until TLC indicates quantitative consumption ofthe starting material (5 h). The catalyst is filtered off with suction,the filtrate is evaporated and the residue is purified by preparativeRP-HPLC (column: Xbridge C18 (waters), gradient water/ACN/NH₄OH, 60°C.).

Yield: 0.39 g (66%), ESI-MS: m/z=231 (M+H)⁺, Specific rotation: [α]_(D)²⁰ (MeOH)=+43°

The following intermediates IV.1A through IV.1F are prepared in asimilar manner to intermediate IV.1:

Nitro- arene ESI-MS Intermediate starting m/z Compound name; # Structurematerial (M + H)⁺ comment IV.1A

III.2G 231 (3R,4R)-4-(3-Amino-6-chloro- pyridin-2-yloxy)-tetrahydro-furan-3-ol; Specific rotation: [α]_(D) ²⁰ (MeOH) = −43° IV.1B

III.2C 230 (3R,4R)-4-(2-Amino-5-chloro- phenoxy)-tetrahydro-furan-3-ol;Solvent is THF IV.1C

III.2B 230 (3S,4S)-4-(2-Amino-5-chloro- phenoxy)-tetrahydro-furan-3-ol;Solvent is THF IV.1D

III.1I 361 (3R,4R)-3-(2-Amino-5-fluoro- phenoxy)-4-methoxy-pyrrolidine-1-carboxylic acid benzyl ester; Solvent is THF, nochromatographic purification IV.1E

III.1K 344 (3R,4R)-3-(3-Amino-pyridin-2- yloxy)-4-methoxy-pyrrolidine-1-carboxylic acid benzyl ester; Solvent is THF, no chromatographicpurification IV.1F

II.1Q 216 rac-trans-4-Fluoro-2-(4-fluoro- tetrahydro-furan-3-yloxy)-phenylamine; solvent is THF

Intermediate IV.2:(3S,4S)-4-(2-Amino-5-fluoro-phenoxy)-tetrahydro-furan-3-ol

Pd/C (10%, 320 mg) is added to the nitroarene starting material(3S,4S)-4-(5-fluoro-2-nitrophenoxy)-tetrahydro-furan-3-ol (intermediateIII.2, 2.95 g; 12.1 mmol) in EtOH (30 ml). The reaction mixture isstirred at RT until TLC indicates quantitative consumption of thestarting material (over night). The catalyst is filtered off withsuction and the filtrate is evaporated.

Yield: 2.36 g (61%), ESI-MS: m/z=214 (M+H)⁺, Specific rotation: [α]_(D)²⁰ (MeOH)=+180

The following intermediates IV.2A through IV.2AA are prepared in asimilar manner to intermediate IV.2:

Nitro- arene ESI-MS Intermediate starting m/z Compound name; # Structurematerial (M + H)⁺ comment IV.2A

III.2A 214 (3R,4R)-4-(2-Amino-5-fluoro- phenoxy)-tetrahydro-furan-3-ol;Specific rotation: [α]_(D) ²⁰ (MeOH) = −17° IV.2B

III.1D 214 rac-cis-4-(2-Amino-5-fluoro- phenoxy)-tetrahydro-furan-3-ol;Solvent is EtOAc IV.2C

III.1A 228 rac-cis-4-Fluoro-2-(4-methoxy- tetrahydro-furan-3-yloxy)-phenylamine; solvent is EtOAc IV.2D

III.1C 197 rac-cis-2-(4-Hydroxy- tetrahydro-furan-3-yloxy)-pyridin-3-ylamine IV.2E

III.1B 211 rac-trans-2-(4-Methoxy- tetrahydro-furan-3-yloxy)-pyridin-3-ylamine; solvent is EtOAc IV.2F

III.2D 197 (3S,4S)-4-(3-Amino-pyridin-2- yloxy)-tetrahydro-furan-3-ol;Solvent is methanol IV.2G

III.2E 197 (3R,4R)-4-(3-Amino-pyridin-2- yloxy)-tetrahydro-furan-3-ol;Solvent is methanol; Specific rotation: [α]_(D) ²⁰ (MeOH) = −50° IV.2H

III.3 243 rac-cis-2-[4-(2-Fluoro-ethoxy)- tetrahydro-furan-3-yloxy]-pyridin-3-ylamine; solvent is EtOAc IV.2I

III.4 242 4-Fluoro-2-(6-methoxy- tetrahydro-pyran-3-yloxy)- phenylamine;Solvent is EtOAc IV.2K

III.1N 211 rac-cis-2-(4-Methoxy- tetrahydro-furan-3-yloxy)-pyridin-3-ylamine IV.2L

III.10A 255 (3S,4S)-1-[3-(2-Amino-5-fluoro-phenoxy)-4-hydroxy-pyrrolidin- 1-yl]-ethanone IV.2M

III.7A 227 (3S,4S)-4-(2-Amino-5-fluoro- phenoxy)-1-methyl-pyrrolidin-3-ol IV.2N

III.2H 291 (3R,4R)-4-(2-Amino-5-fluoro- phenoxy)-1-methanesulfonyl-pyrrolidin-3-ol; Solvent is THF IV.2O

III.10 255 (3R,4R)-1-[3-(2-Amino-5- fluoro-phenoxy)-4-hydroxy-pyrrolidin-1-yl]-ethanone; Solvent is THF IV.2P

III.7 227 (3R,4R)-4-(2-Amino-5-fluoro- phenoxy)-1-methyl-pyrrolidin-3-ol; Solvent is MeOH IV.2Q

III.1M 410 (3S,4S)-3-(3-Amino-pyridin-2- yloxy)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1- carboxylic acid tert-butyl ester IV.2R

III.1L 410 (3R,4R)-3-(3-Amino-pyridin-2- yloxy)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1- carboxylic acid tert-butyl ester IV.2S

III.2I 238 (3R,4R)-1-[3-(3-Amino-pyridin-2-yloxy)-4-hydroxy-pyrrolidin-1- yl]-ethanone IV.2T

III.2K 274 (3R,4R)-4-(3-Amino-pyridin-2- yloxy)-1-methanesulfonyl-pyrrolidin-3-ol IV.2U

III.1G 427 (3S,4S)-3-(2-Amino-5-fluoro- phenoxy)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1- carboxylic acid tert-butyl ester IV.2V

III.1F 427 (3R,4R)-3-(2-Amino-5-fluoro- phenoxy)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1- carboxylic acid tert-butyl ester IV.2W

III.7B 210 (3R,4R)-4-(3-Amino-pyridin-2- yloxy)-1-methyl-pyrrolidin-3-olIV.2X

III.2L 291 (3S,4S)-4-(2-Amino-5-fluoro- phenoxy)-1-methanesulfonyl-pyrrolidin-3-ol; Solvent is THF IV.2Y

III.1O 224 exo-6-(2-amino-5-fluoro- phenoxy)-2-oxabicyclo[2.2.1.]heptane; solvent is EtOAc IV.2Z

III.1P 224 endo-2-(2-amino-5-fluoro- phenoxy)-7-oxabicyclo[2.2.1]heptane; solvent is EtOAc IV.2AA

V.16 184 2-Amino-6-difluoromethoxy- benzonitrile

Intermediate IV.3:rac-trans-4-(2-Amino-5-fluoro-phenoxy)-tetrahydro-furan-3-carbonitrile

A mixture ofrac-trans-4-(5-fluoro-2-nitro-phenoxy)-tetrahydro-furan-3-carbonitrile(intermediate III.1E, 0.58 g; 2.30 mmol), tin(II)chloride dihydrate(2.53 g; 11.3 mmol) and EtOAc (20 ml) is refluxed for 1 h. The mixtureis diluted with further EtOAc, then poured into NaOH solution (4N). Theorganic layer is separated, dried with sodium sulphate and evaporated.

Yield: 419 mg (82%), ESI-MS: m/z=223 (M+H)⁺

Intermediate IV.4 and intermediate IV.4A: pure enantiomers ofcis-4-(2-Amino-5-fluoro-phenoxy)-tetrahydro-fu ran-3-ol

Racemic cis-4-(2-Amino-5-fluoro-phenoxy)-tetrahydro-furan-3-ol(intermediate IV.2B, 3.75) is separated by chiral HPLC into pureenantiomers. Absolute configuration is not determined. HPLC conditions:CHIRALCEL®OJ-H, 5 μM (Daicel), 40° C., 150 bar backpressure, 85% scCO2,15% 2-Propanol+0.2% DEA, 4 ml/min Enantiomer 1, intermediate IV.4:Yield: 1.55 g (41%), R_(t)(HPLC): 2.15 min Enantiomer 2, intermediateIV.4A: Yield: 1.46 g (39%), R_(t)(HPLC): 2.54 min

The following Intermediates are prepared according to the givenreferences:

Name Structure Reference V.1

WO 2008/141843 A1 V.2

WO 2008/141843 A1 V.3

Adaptation of Organic Letters, 2004, vol. 6, pp. 1305-1307 V.4

Adaptation of WO 2008/141843 V.5

WO 2008/141843 A1 V.6

US2005/228027 A1 V.7

Adaptation of Organic Letters, 2004, vol. 6, pp. 1305-1307 V.8

Organic Letters, 2004, vol. 6, pp. 1305-1307 V.9

Organic Letters, 2004, vol. 6, pp. 1305-1307 V.10

Adaptation of Organic Letters, 2004, vol. 6, pp. 1305-1307 V.11

Adaptation of WO 2008/141843 V.12

Adaptation of Organic Letters, 2004, vol. 6, pp. 1305-1307 V.13

Adaptation of Organic Letters, 2004, vol. 6, pp. 1305-1307 V.14

WO2011/62885 V.15

Adaptation of WO 2008/141843 V.16

WO2009/92590 V.17

US5750471 A1

Intermediate VI.1:2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenol

6.7 g (25 mmol) of II.1A and 5.7 g (26 mmol) of V.17 are dissolved inacetic acid and heated to 100° C. for 1 h. After cooling to RT thereaction mixture is diluted with water and the precipitate is filteredoff and washed with water. The crude product is treated with 80 mlethanol, filtered and dried yieldingN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine.

Yield: 7.1 g (65%), ESI-MS: m/z=438 (M+H)⁺, R_(t)(HPLC): 1.12 min(HPLC-M).

3.1 g (7 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine, 0.8g (8.8 mmol) dimethylsulphoximine (V.1), 0.4 g (1.4 mmol)2-(di-t-butylphosphino) biphenyl, 0.5 g (0.5 mmol) Pd₂dba₃ and 1.0 g(10.2 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 4.5h. After cooling to RT the reaction mixture is filtered, diluted withwater and extracted with EtOAc. The organic layers are pooled, dried andevaporated. The residue is purified by FC giving rise toN-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-amine.

Yield: 2.8 g (88%), ESI-MS: m/z=451 (M+H)⁺

3.5 g (7.8 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-aminein DCM are cooled to 0° C., 0.9 ml (9.3 mmol) boron tribromide are addeddropwise and the reaction mixture is stirred for 15 min. Water is addedcautiously and the aqueous layer is separated and extracted with DCM.The organic phases are pooled, washed with water, dried and evaporated.The residue is treated with isopropanol, filtered and dried.

Yield: 2.5 g (89%), ESI-MS: m/z=361 (M+H)⁺, R_(t)(HPLC): 1.12 min(HPLC-T)

Intermediate VI.2:2-[[7-[(1-oxothiolan-1-ylidene)amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-pheonol.

Is prepared in a similar manner as intermediate VI.1 using II.1A, V.17and V.5. ESI-MS: m/z=387 (M+H)⁺, R_(t)(HPLC): 0.56 min (HPLC-M)

The following intermediates can be obtained according to the givenliterature:

Intermediate Chemical name Literature VII.1 rac-cis-3-hydroxy-4-methoxy-Journal of the tetrahydrofuran American Chemical Society, 1970, vol. 92,pp. 4699-4706 VII.2 rac-trans-3-hydroxy-4-methoxy- Journal of thetetrahydrofuran Chemical Society, 1959, pp. 248-254 VII.3(3S,4S)-4-(tert-butyl-dimethyl- WO2013/55577; diolsilanyloxy)-tetrahydro-furan-3-ol starting material: Synthesis, 1992,pp. 951-953 VII.4 (3R,4R)-4-(tert-butyl-dimethyl- WO2013/55577; diolsilanyloxy)-tetrahydro-furan-3-ol starting material: Synthesis, 1992,pp. 951-953 VII.5 rac-cis-6-methoxy-3,6-dihydro- Journal of Organic2H-pyran-3-ol Chemistry, 1997, vol. 62(5), pp. 1257-1263 VII.6rac-trans-3-cyano-4-hydroxy- U.S. Pat. No. tetrahydrofuran 5,602,118VII.7 (3R,4R)-3-(tert-butyl-dimethyl- Tetrahedron:silanyloxy)-4-hydroxy-pyrrolidine- Asymmetry, 1-carboxylic acidtert-butyl ester 2001, vol. 12, pp. 1793-1799 VII.8(3S,4S)-3-(tert-butyl-dimethyl- Tetrahedron:silanyloxy)-4-hydroxy-pyrrolidine- Asymmetry, 1-carboxylic acidtert-butyl ester 2001, vol. 12, pp. 1793-1799 VII.9(3S,4S)-1-benzyl-4-(tert-butyl- Tetrahedron:dimethyl-silanyloxy)-pyrrolidin- Asymmetry, 3-ol 2001, vol. 12, pp.1793-1799 VII.10 (3R,4R)-3-hydroxy-4-methoxy- US2004/19065pyrrolidine-1-carboxylic acid benzyl ester VII.11(3S,4S)-4-benzyloxy-tetrahydro- Tetrahedron Letters, furan-3-ol 1997,vol. 38(34), pp. 5945-5948 (solvent is toluene); diol starting material:Synthesis, 1992, pp. 951-953 VII.12 exo-2-oxabicyclo[2.2.1.]heptan- J.Am. Chem. Soc., 6-ol vol. 94(8), pp. 2707ff VII.13endo-7-oxabicyclo[2.2.1]heptan- J. Am. Chem. Soc., 2-ol vol. 107(25),pp. 2546ff

Intermediate VIII.1: rac-trans-4-fluoro-3-hydroxytetrahydrofurane

A mixture of 3,6-dioxa-bicyclo[3.1.0]hexane (1.00 g; 12 mmol) andtriethylamine trihydrofluoride (2.81 g; 17 mmol) is stirred at 120° C.over night. The mixture is allowed to cool to RT, quenched withsaturated sodium bicarbonate solution and stirred for 1 h, thenextracted with DCM/2-propanol (5:1). The organic layer is separated,dried and evaporated to yield the crude product which is further reactedwithout chromatographic purification.

Yield: 510 mg (60%)

Methods of Preparation of Final Compounds

General Procedure 1 (P1) for Examples Shown in Table 1:

Equimolar amounts of the respective intermediates II and IV aredissolved in AcOH and heated to the given temperature for the giventime. The reaction mixture is diluted with water and saturated aqueousNaHCO₃-solution. An alternative workup comprises evaporation of thereaction mixture and treatment of the residue with MeOH and water. Incase the product precipitates it is filtered off, otherwise the mixtureis extracted with EtOAc. The organic phases are pooled dried andevaporated. If required, the crude product is further purified by FC orHPLC.

The following examples in table 1 (example number given in column #) areprepared according to P1, details are given in the column synthesiscomment.

TABLE 1 Starting ESI-MS HPLC materials m/z R_(t) Synthesis # StructureII, IV M + H⁺ Method comment 1.1

II.2A IV.3 482 1.20 min HPLC- W 65° C. 1.5 h 1.2

II.2 IV.3 456 0.43 min HPLC- W 65° C. 2 h 1.3

II.3 IV.2B 467 0.41 min HPLC- W 80° C. 3 h 1.4

II.3 IV.2C 481 0.46 min HPLC- W 80° C. 3 h 1.5

II.3A IV.2B 493 0.44 min HPLC- W 80° C. 3 h 1.6

II.3A IV.2C 507 0.50 min HPLC- W 80° C. 3 h 1.7

II.3B IV.2 479 0.43 min HPLC- W 75° C. 3 h 1.8

II.3 IV.2 467 0.42 min HPLC- W 75° C. 3 h 1.9

II.3A IV.2 493 0.44 min HPLC- W 75° C. 3 h 1.10

II.4 IV.2 473 0.42 min HPLC- K 80° C. 5 h 1.11

II.3D IV.2 499 0.43 min HPLC- K 80° C. 5 h 1.12

II.3E IV.2 501 0.46 min HPLC- K 80° C. 5 h 1.13

II.3B IV.2F 462 0.42 min HPLC- W 75° C. 3 h 1.14

II.3 IV.2F 450 0.41 min HPLC- W 75° C. 3 h 1.15

II.3A IV.2F 476 0.43 min HPLC- W 75° C. 3 h 1.16

II.3B IV.1 496 0.92 min HPLC- M 75° C. 3 h 1.17

II.3A IV.1 510 0.93 min HPLC- M 75° C. 3 h 1.18

II.3C IV.2 511 0.57 min HPLC- N 80° C. 3 h 1.19

II.3 IV.1 484 0.90 min HPLC- M 75° C. 3 h 1.20

II.2B IV.1 494 0.90 min HPLC- M 75° C. 3 h 1.21

II.2C IV.1 468 0.87 min HPLC- M 75° C. over night 1.22

II.3B IV.2A 479 0.88 min HPLC- M 75° C. 3 h 1.23

II.2 IV.1C 463 0.85 min HPLC- M 75° C. 3 h 1.24

II.2D IV.1 480 0.89 min HPLC- M 75° C. 3 h 1.25

II.3A IV.2A 493 0.85 min HPLC- M 75° C. 3 h 1.26

II.3 IV.2A 467 0.89 min HPLC- M 75° C. 3 h 1.27

II.2A IV.1C 489 0.89 min HPLC- M 75° C. 3 h 1.28

II.3F IV.2 527 0.56 min HPLC- X 80° C. 5 h 1.29

II.2E IV.1C 475 0.88 min HPLC- M 75° C. 3 h 1.30

II.2E IV.1B 475 0.88 min HPLC- M 75° C. 3 h 1.31

II.2 IV.1B 463 0.86 min HPLC- M 75° C. 3 h 1.32

II.2A IV.1B 489 0.89 min HPLC- M 75° C. 3 h 1.33

II.3G IV.2 465 0.60 min HPLC- V 70° C. 4 h 1.34

II.3B IV.4 479 0.52 min HPLC- W 75° C. 5 h; see footnote a 1.35

II.3B IV.4A 479 0.52 min HPLC- W 75° C. 5 h; see footnote a 1.36

II.2E IV.4 459 1.07 min HPLC- F 75° C. 5 h; see footnote a 1.37

II.2E IV.4A 459 1.08 min HPLC- F 75° C. 5 h; see footnote a a:Enantiomerically pure cis enantiomer; absolute stereochemistry unknownand assigned arbitrarily. 1.36 and 1.37 are optical antipodes.General Procedure 2 (P2) for Examples Shown in Table 2:

1 eq of aryl bromide (II), 1.2 eq of sulphoximine (V), 25 mol %2-(di-t-butylphosphino) biphenyl, 8 mol % Pd₂dba₃ and 1.4 eq sodiumtert-butoxide are mixed with dioxane and heated to the given temperaturefor the given time. The reaction mixture is concentrated and the crudeproduct purified by HPLC or FC.

General Procedure 3 (P3) for Examples Shown in Table 2:

1 eq of aryl bromide, 1.25 eq of sulphoximine, 20 mol % rac-BINAP, 15mol % Pd(OAc)₂ and 1.4 eq Cs₂CO₃ are suspended in toluene and heated toheated to the given temperature for the given time. The reaction mixtureis concentrated and the crude product purified by HPLC or FC.

To obtain the following examples shown in table 2 (example number givenin column #), the corresponding 7-bromo quinazoline (aryl bromide) isprepared according to P1 from the respective intermediates II and IVfollowed by coupling according to P2 or P3 with the respectivesulphoximine V as indicated. Further details are given in the columnsynthesis comment.

TABLE 2 Starting ESI-MS HPLC materials m/z R_(t) Synthesis # StructureII, IV, V M + H⁺ Method comment 2.1

II.1A IV.2K V.1 444 0.46 min HPLC- W P2 80° C. 3 h 2.2

II.1A IV.2K V.5 470 1.11 min HPLC- F P2 80° C. 3 h 2.3

II.1A IV.2D V.5 456 0.99 min HPLC- F P2 80° C. 3 h 2.4

II.1A IV.2D V.1 430 0.95 min HPLC- F P2 80° C. 3 h 2.5

II.1A IV.2P V.5 486 0.81 HPLC- P P2 80° C. 3 h 2.6

II.1A IV.2P V.1 460 0.77 HPLC- P P2 80° C. 3 h 2.7

II.1A IV.2B V.1 447 1.03 min HPLC- F P2 80° C. 2 h 2.8

II.1A IV.2B V.5 473 1.07 min HPLC- F P2 80° C. 2 h 2.9

II.1A IV.2C V.1 461 1.13 min HPLC- F P2 80° C. 2 h 2.10

II.1A IV.2C V.5 487 1.19 min HPLC- F P2 80° C. 2 h 2.11

II.1A IV.2N V.1 524 0.68 min HPLC- J P2 80° C. 3 h 2.12

II.1A IV.2N V.5 550 0.81 min HPLC- P P2 80° C. 3 h 2.13

II.1A IV.2O V.5 514 0.67 HPLC- M P2 80° C. 3 h 2.14

II.1A IV.1D V.1 594 1.40 min HPLC- F P2 80° C. 2 h 2.15

II.1A IV.1D V.5 620 1.44 min HPLC- F P2 80° C. 2 h 2.16

II.1A IV.1E V.5 603 1.43 min HPLC- F P2 80° C. 2 h 2.17

II.1A IV.1E V.1 577 0.57 HPLC- W P2 80° C. 2 h 2.18

II.1A IV.2W V.5 469 0.53 min HPLC- N P2 80° C. 3 h 2.19

II.1A IV.2W V.1 443 0.49 min HPLC- N P2 80° C. 3 h 2.20

II.1A IV.2T V.1 507 0.65 min HPLC- M P2 80° C. 3 h 2.21

II.1A IV.2S V.1 471 0.62 min HPLC- M P2 80° C. 3 h 2.22

II.1A IV.2T V.5 533 0.68 min HPLC- M P2 80° C. 3 h 2.23

II.1A IV.2S V.5 497 0.65 min HPLC- M P2 80° C. 3 h 2.24

II.1A IV.2F V.5 456 1.16 min HPLC- F P2 80° C. 3 h 2.25

II.1A IV.2H V.5 502 0.78 min HPLC- M P2 80° C. 3 h 2.26

II.1A IV.2H V.1 476 0.75 min HPLC- M P2 80° C. 3 h 2.27

II.1A IV.2 V.1 447 1.06 min HPLC- F P2 80° C. 3 h 2.28

II.1A IV.2F V.1 430 0.92 min HPLC- F P2 80° C. 3 h 2.29

II.1A IV.2 V.5 473 1.11 min HPLC- F P2 80° C. 3 h 2.30

II.1 IV.2D V.5 460 1.14 min HPLC- F P2 80° C. 2 h 2.31

II.1A IV.2D V.6 470 0.63 min HPLC- V P2 80° C. 2 h 2.32

II.1A IV.2D V.4 442 0.59 min HPLC- V P2 80° C. 2 h 2.33

II.1 IV.2D V.4 446 1.11 min HPLC- F P2 80° C. 2 h 2.34

II.1A IV.2E V.1 444 0.50 min HPLC- X P2 80° C. 2 h 2.35

II.1A IV.2E V.4 456 0.69 min HPLC- B P2 80° C. 2 h 2.36

II.1A IV.2 V.4 459 0.40 min HPLC- W P2 80° C. 3 h 2.37

II.1A IV.2 V.2 461 0.41 min HPLC- W P2 80° C. 3 h 2.38

II.1A IV.2 V.6 487 0.43 min HPLC- W P2 80° C. 3 h 2.39

II.1A IV.2E V.5 470 0.69 min HPLC- B P2 80° C. 2 h 2.40

II.1A IV.1 V.1 464 0.73 min HPLC- M P2 60° C. 3 h 2.41

II.1A IV.2F V.4 442 0.98 min HPLC- F P2 80° C. 3 h 2.42

II.1A IV.1 V.5 490 0.76 min HPLC- M P2 80° C. 3 h 2.43

II.1A IV.1 V.4 476 0.76 min HPLC- M P2 80° C. 3 h 2.44

II.1 IV.2F V.5 460 0.99 min HPLC- F P2 80° C. 3 h 2.45

II.1A IV.2 V.1 447 1.02 min HPLC- F P2 80° C. 3 h 2.46

II.1A IV.2A V.5 473 1.07 min HPLC- F P2 80° C. 3 h 2.47

II.1A IV.2A V.4 459 1.05 min HPLC- F P2 80° C. 3 h 2.48

II.1A IV.1A V.1 464 1.07 min HPLC- F P2 80° C. 3 h 2.49

II.1A IV.2G V.4 442 0.98 min HPLC- F P2 80° C. 3 h 2.50

II.1A IV.2G V.5 456 1.00 min HPLC- F P2 80° C. 3 h 2.51

II.1A IV.2G V.1 430 0.95 min HPLC- F P2 80° C. 3 h 2.52

II.1 IV.2B V.1 451 0.59 min HPLC- V P2 80° C. over night 2.53

II.1A IV.1A V.4 476 1.09 min HPLC- F P2 80° C. 3 h 2.54

II.1A IV.1A V.5 490 0.77 min HPLC- M P2 70° C. over night 2.55

II.1 IV.2 V.1 451 0.60 min HPLC- V P2 80° C. over night 2.56

II.1A IV.2I V.4 487 0.50 min HPLC- AA P2 80° C. 4.5 h 2.57

II.1 IV.2C V.1 465 0.44 min HPLC- W P2 80° C. 2 h 2.58

II.1 IV.2C V.5 591 0.46 min HPLC- W P2 80° C. 2 h 2.59

II.1A IV.2X V.1 524 1.02 min HPLC- F P2 80° C. 3 h 2.60

II.1A IV.2X V.5 550 1.07 min HPLC- F P2 80° C. 3 h 2.61

II.1A IV.2M V.5 486 1.06 min HPLC- M P2 80° C. 3 h 2.62

II.1A IV.2M V.1 460 0.85 min HPLC- F P2 80° C. 3 h 2.63

II.1A IV.2I V.1 475 1.21 min HPLC- D P2 80° C. 4.5 h 2.64

II.1A IV.2B foot- note a 509 0.58 min HPLC- X P2 90° C. 3 h 2.65

II.1A IV.2B V.10 517 0.54 min HPLC- X P2 90° C. 3 h 2.66

II.1 IV.2 V.5 477 0.65 min HPLC- V P2 90° C. 3 h 2.67

II.1A IV.2B V.4 459 0.51 min HPLC- X P2 90° C. 3 h 2.68

II.1A IV.2B V.8 489 0.59 min HPLC- X P2 90° C. 3 h 2.69

II.1 IV.2 V.11 514 0.65 min HPLC- V P2 90° C. 3 h 2.70

II.1A IV.2B V.11 510 0.51 min HPLC- X P2 90° C. 3 h 2.71

II.1A IV.2B V.3 475 0.54 min HPLC- X P2 90° C. 3 h 2.72

II.1A IV.2B V.7 473 0.53 min HPLC- X P2 90° C. 3 h 2.73

II.1 IV.2 V.7 477 0.52 min HPLC- X P2 90° C. 3 h 2.74

II.1A IV.2 V.3 475 0.51 min HPLC- X P2 90° C. 3 h 2.75

II.1A IV.2 V.9 509 0.50 min HPLC- X P2 90° C. 3 h 2.76

II.1A IV.2B V.12 503 0.47 min HPLC- X P2 90° C. 3 h 2.77

II.1A IV.2 V.7 473 0.50 min HPLC- X P2 90° C. 3 h 2.78

II.1A IV.2 V.10 517 0.50 min HPLC- X P2 90° C. 3 h 2.79

II.1A IV.2 V.8 489 0.55 min HPLC- X P2 90° C. 3 h 2.80

II.1 IV.2 V.13 491 0.51 min HPLC- X P2 90° C. 3 h 2.81

II.1A IV.2 V.11 510 0.48 min HPLC- X P2 90° C. 3 h 2.82

II.1A IV.2 V.12 503 0.46 min HPLC- X P2 90° C. 3 h 2.83

II.1A IV.2B V.13 487 0.52 min HPLC- X P2 90° C. 3 h 2.84

II.1 IV.2 V.12 507 0.46 min HPLC- X P2 90° C. 3 h 2.85

II.1A IV.2 V.13 487 0.51 min HPLC- X P2 90° C. 3 h 2.86

II.1 IV.2 V.9 513 0.73 min HPLC- V P2 90° C. 3 h 2.87

II.1 IV.2B V.4 463 0.64 min HPLC- V P2 90° C. 3 h 2.88

II.1 IV.2 V.10 521 0.66 min HPLC- V P2 90° C. 3 h 2.89

II.1 IV.2B V.11 514 0.51 min HPLC- X P2 90° C. 3 h 2.90

II.1 IV.2B V.3 479 0.68 min HPLC- V P2 90° C. 3 h 2.91

II.1 IV.2B V.7 477 0.65 min HPLC- V P2 90° C. 3 h 2.92

II.1 IV.2 V.4 463 0.64 min HPLC- V P2 90° C. 3 h 2.93

II.1 IV.2B V.5 477 0.64 min HPLC- V P2 90° C. 3 h 2.94

II.1 IV.2B V.12 507 0.60 min HPLC- V P2 90° C. 3 h 2.95

II.1 IV.2B V.9 513 0.73 min HPLC- V P2 90° C. 3 h 2.96

II.1 IV.2B V.13 491 0.51 min HPLC- X P2 90° C. 3 h 2.97

II.1 IV.2 V.15 514 0.65 min HPLC- V P2 90° C. 3 h 2.98

II.1A IV.2Z V.1 457 0.69 min HPLC- A P2 90° C. 1 h 2.99

II.1A IV.2Y V.1 457 0.69 min HPLC- A P2 90° C. 1 h 2.100

II.1A IV.1F V.1 449 0.47 min HPLC- W P2 80° C. 12 h 2.101

II.1A IV.1F V.5 475 0.50 min HPLC- W P2 80° C. 12 h 2.102

II.1A IV.2O V.1 488 0.65 min HPLC- M P2 80° C. 3 h a: Example 2.64:(S)-enantiomer of intermediate V.9 (which is commercially available)applied. Stereochemistry: racemic cis at THF moiety; (S)-configurationat sulfoximine moiety.General Procedure 4 (P4) for Examples Shown in Table 3:

The starting material is dissolved in the solvent mixture indicated andstirred at the given temperature over night. The reaction mixture isconcentrated and if necessary the crude product purified by HPLC.

To obtain the following examples (example number given in column #)shown in table 3, the corresponding 7-bromo quinazoline (aryl bromide)is prepared according to P1 from the respective intermediates II and IVfollowed by coupling according to P2 or P3 with the respectivesulphoximine V as indicated. Without prior chromatographic purification,the crude product from P2 or P3 is then deprotected according to P4applying the solvent mixture AcOH/THF/water 3:1:1. Further details aregiven in the column synthesis comment.

TABLE 3 Starting ESI-MS materials m/z HPLC R_(t) Synthesis # StructureII, IV, V M + H⁺ Method comment 3.1

II.1A IV.2R V.5 455 0.31 min HPLC-W P2 80° C. 3 h; P4 80° C. 3.2

II.1A IV.2R V.1 429 0.64 min HPLC-P P2 80° C. 3 h; P4 80° C. 3.3

II.1A IV.2Q V.5 455 0.31 min HPLC-W P2 80° C. 3 h; P4 80° C. 3.4

II.1A IV.2V V.1 446 0.66 min HPLC-M P2 80° C. 3 h; P4 100° C. 3.5

II.1A IV.2V V.5 472 0.68 min HPLC-M P2 80° C. 3 h; P4 100° C. 3.6

II.1A IV.2U V.5 427 0.69 min HPLC-M P2 80° C. 3 h; P4 100° C. 3.7

II.1A IV.2U V.1 446 0.66 HPLC-M P2 80° C. 3 h; P4 100° C.General Procedure 5 (P5) for Examples Shown in Table 4:

A mixture of the respective starting material, palladium on charcoal(10%, 0.1 weight equivalents) and EtOH is stirred under hydrogenatmosphere (30 psi H₂) until HPLC analytics indicates completeconsumption of starting material. Insolubles are filtered off withsuction, the filtrate is evaporated and the residue is purified by FC(DCM/MeOH/NH₄OH).

TABLE 4 ESI-MS Starting m/z HPLC R_(t) Synthesis # Structure materialM + H⁺ Method comment 4.1

2.14 460 0.92 min HPLC-F 4.2

2.15 486 0.96 min HPLC-F 4.3

2.15 514 1.02 min HPLC-F Obtained as a by- product in the synthesis of4.2 4.4

2.16 469 0.92 min HPLC-F 4.5

2.17 443 0.89 min HPLC-FGeneral Procedure 6 (P6) for Examples Shown in Table 5:

A mixture of the respective starting material (1 eq.), the alkylatingagent (3 eq.), triethylamine (5 eq.) and ACN is stirred at 120° C. for 3h (closed vial, microwave heating). Volatiles are evaporated, theresidue is taken up in DCM and extracted with water. The organic layeris separated, dried and evaporated. The residue is purified by RP-HPLC.

TABLE 5 ESI-MS Starting m/z HPLC R_(t) Alkylating # Structure materialM + H⁺ Method agent 5.1

4.2 550 0.42 min HPLC-W 1,1-difluoro- 2- iodoethane 5.2

4.5 507 0.36 min HPLC-W 1,1-difluoro- 2- iodoethane 5.3

4.5 489 0.32 min HPLC-W 1-Bromo-2- fluoroethane 5.4

4.1 524 0.41 min HPLC-W 1,1-difluoro- 2- iodoethane 5.5

4.4 533 0.38 min HPLC-W 1,1-difluoro- 2- iodoethaneGeneral Procedure 7 (P7) for Examples Shown in Table 6:

To a mixture of the respective starting material (1 eq.), triethylamine(3 eq.) and DCM cooled with an ice-bath is added the acylating agent (1eq.). The mixture is stirred at RT over night. Volatiles are evaporated,the residue is taken up in DCM and extracted with water. The organiclayer is separated, dried and evaporated. The residue is purified byRP-HPLC.

TABLE 6 ESI-MS Starting m/z HPLC R_(t) Acylating # Structure materialM + H⁺ Method agent 6.1

4.1 502 1.07 min HPLC-F Acetyl chloride 6.2

4.2 528 1.10 min HPLC-F Acetyl chloride 6.3

4.5 485 0.40 min HPLC-F Acetyl chloride 6.4

4.2 564 1.20 min HPLC-F Methane- sulphonyl chloride 6.5

4.4 547 0.44 min HPLC-F Methane- sulphonyl chloride 6.6

4.5 521 0.43 min HPLC-W Methane- sulphonyl chloride 6.7

4.1 538 1.14 min HPLC-F Methane- sulphonyl chloride 6.8

4.4 511 0.41 min HPLC-W Acetyl chloride 6.9

2.7 489 0.47 min HPLC-W Acetyl chloride 6.10

3.3 539 0.42 min HPLC-W Acetyl chloride (2 eq.)General Procedure 8 (P8) for Examples Shown in Table 7:

To a solution of the respective starting material (1 eq.) in DMF cooledto 0° C. is added sodium hydride (55% in mineral oil, 1.2 eq.). Themixture is stirred for 30 min, then the respective alkylating agent (1eq.) is added. The mixture is stirred over night without furthercooling. Water is added and the mixture is extracted with DCM. Theorganic layer is separated, dried, and evaporated. The residue ispurified by RP-HPLC or FC.

TABLE 7 ESI-MS Starting m/z HPLC R_(t) Alkylating # Structure materialM + H⁺ Method agent 7.1

2.7 505 0.49 min HPLC-W 1-chloro-2- methoxy- ethane 7.2

2.7 501 0.54 min HPLC-W Chloro- methyl- cyclopropane 7.3

2.7 503 0.55 min HPLC-N 3-bromo- oxetaneGeneral Procedure 9 (P9) for Examples Shown in Table 8:

A mixture of the respective starting material (1.0 eq.), cesiumcarbonate (1.2 eq.), methanol (40 weight equivalents) and dioxane isstirred at 90° C. for 2 h. Water is added. Products that precipitate arefiltered and dried. Alternatively the mixture is extracted with DCM, theorganic layer is separated, dried and evaporated. The residue ispurified by RP-HPLC or FC.

TABLE 8 ESI-MS Starting m/z HPLC R_(t) Synthesis # Structure materialM + H⁺ Method comment 8.1

1.20 506 1.15 min HPLC-F 8.2

1.21 480 1.12 min HPLC-F 8.3

2.44 472 1.05 min HPLC-F 8.4

2.33 458 0.39 min HPLC-W 8.5

2.30 472 0.41 min HPLC-W

To obtain the following examples shown in table 9 (example number givenin column #), the corresponding 5-fluoro-7-bromo quinazoline (arylbromide) is prepared according to P1 from the respective intermediatesII and IV followed by introduction of the 5-alkoxy group according to P9(unless indicated otherwise, the alcohol applied is methanol), finallyfollowed by the introduction of the sulphoximine moiety according to P2applying the respective intermediates V as indicated. Further detailsare given in the column synthesis comment.

TABLE 9 Starting ESI-MS materials m/z HPLC R_(t) Synthesis # StructureII, IV, V M + H⁺ Method comment 9.1

II.1 IV.2C V.1 477 0.45 min HPLC-W 9.2

II.1 IV.2C V.5 503 0.48 min HPLC-W 9.3

II.1 IV.2B V.1 463 0.59 min HPLC-V 9.4

II.1 IV.2 V.1 463 0.59 min HPLC-V 9.5

II.1 IV.1 V.4 492 0.49 min HPLC-W 9.6

II.1 IV.2 V.1 477 0.64 min HPLC-V EtOH applied in P9 9.7

II.1 IV.2 V.1 500 1.20 min HPLC-F 2,2- difluoro- ethanol (20 eq.)applied in P9 9.8

II.1 IV.2 V.1 495 0.80 min HPLC-M 2-fluoro- ethanol (20 eq.) applied inP9 9.9

II.1 IV.2 V.3 491 0.67 min HPLC-V 9.10

II.1 IV.2 V.4 475 0.63 min HPLC-V 9.11

II.1 IV.2 V.10 533 0.64 min HPLC-V 9.12

II.1 IV.2B V.11 526 0.63 min HPLC-V 9.13

II.1 IV.2B V.5 489 0.64 min HPLC-V 9.14

II.1 IV.2 V.11 526 0.64 min HPLC-V 9.15

II.1 IV.2B V.10 533 0.64 min HPLC-V 9.16

II.1 IV.2B V.4 475 0.62 min HPLC-V 9.17

II.1 IV.2B V.7 489 0.64 min HPLC-V 9.18

II.1 IV.2 V.8 505 0.72 min HPLC-V 9.19

II.1 IV.2B V.8 505 0.71 min HPLC-V 9.20

II.1 IV.2B V.3 491 0.66 min HPLC-V 9.21

II.1 IV.2B V.9 525 0.71 min HPLC-V 9.22

II.1 IV.2 V.7 489 0.65 min HPLC-V 9.23

II.1 IV.2B V.13 503 0.68 min HPLC-V 9.24

II.1 IV.2 V.13 503 0.69 min HPLC-V 9.25

II.1 IV.2B V.12 519 0.59 min HPLC-V 9.26

II.1 IV.2 V.12 519 0.59 min HPLC-V 9.27

II.1 IV.2B V.15 526 0.63 min HPLC-V 9.28

II.1 IV.2 V.9 525 0.71 min HPLC-V 9.29

II.1 IV.2 V.5 489 0.64 min HPLC-V 9.30

II.1 IV.2 V.15 526 0.64 min HPLC-V

To obtain the following examples shown in table 10 (example number givenin column #), the corresponding 7-bromo quinazoline (aryl bromide) isprepared according to P1 from the respective intermediates II and IVfollowed by alkylation of the hydroxy group according to P8 with thealkylating agent given in the column ‘synthesis comment’, finallyfollowed by the introduction of the sulphoximine moiety according to P2applying the respective intermediates V as indicated. Further detailsare given in the column synthesis comment.

TABLE 10 Starting ESI-MS materials m/z HPLC R_(t) Synthesis # StructureII, IV, V M + H+ Method comment 10.1

II.1A IV.2B V.5 519 1.21 min HPLC-F 1-bromo- 2-fluoro- ethane applied inP8 10.2

II.1A IV.2B V.1 493 1.15 min HPLC-F 1-bromo- 2-fluoro- ethane applied inP8 10.3

II.1A IV.2B V.1 511 0.47 min HPLC-W 1-bromo- 2,2- difluoro- ethaneapplied in P8 10.4

II.1A IV.2B V.5 537 0.49 min HPLC-W 1-bromo- 2,2- difluoro- ethaneapplied in P8General Procedure 10 (P10) for Examples Shown in Table 11:

A mixture of the amine starting material (1 eq.), formaldehyde (37% aq.solution; 2 eq.), and sodium triacetoxyborohydride (1.2 eq.) inTHF/sodium citrate buffer pH5 (9:1) is stirred at RT for 1 h. Volatilesare evaporated, the residue is taken up in DCM and extracted with water.The organic layer is separated, dried and evaporated. The residue ispurified by FC (DCM/MeOH/NH₄OH).

TABLE 11 Amine ESI-MS starting m/z HPLC R_(t) Synthesis # Structurematerial M + H+ Method comment 11.1

4.1 474 0.34 min HPLC-W 11.2

4.2 500 0.36 min HPLC-W 11.3

4.4 483 0.34 min HPLC-W 11.4

4.5 457 0.88 min HPLC-F

The following examples shown in table 12 (example number given in column#), are prepared according to P4 from the starting materials and underthe conditions indicated.

TABLE 12 ESI-MS Solvent Starting m/z HPLC R_(t) mixture and # Structurematerial M + H⁺ Method conditions 12.1

2.56 473 0.44 min HPLC-AA HOAc/water 1:1; 24 h; 80° C. 12.2

2.63 461 1.09 min HPLC-D H₂SO₄/water 1:9; over night; RTGeneral Procedure 11 (P11) for Examples Shown in Table 13:

A mixture of the phenol starting material (1 eq.), the alcohol startingmaterial (1.5 eq.), triphenylphosphine (3 eq.), and THF is stirred at RTfor 10 min. Di-tert-butyl azodicarboxylate (3 eq.) is added and themixture is stirred at RT over night. Volatiles are evaporated and theresidue is purified by HPLC.

TABLE 13 Phenol and alcohol ESI-MS starting m/z HPLC R_(t) Synthesis #Structure materials M + H+ Method comment 13.1

VI.1 VII.5 473 1.22 min HPLC-D 13.2

VI.1 VII.1 461 0.76 min HPLC-J Dioxane is solvent 13.3

VI.2 VII.11 563 0.57 min HPLC-F Diisopropyl azodi- carboxylate applied;N- methyl- pyrrolidone is solventGeneral Procedure 12 (P12) for Examples Shown in Table 14:

Racemic starting material is separated by chiral HPLC into pureenantiomers. Absolute configuration is not determined but assignedarbitrarily. All chiral HPLC-separations are run at 40° C. with abackpressure of 150 bar.

TABLE 14 Racemic ESI-MS starting m/z # Structure material M + H⁺ ChiralHPLC conditions 14.1

2.2  470 Column: CHIRALPAK ® AD-H, 5 μM (Daicel); 10 × 250 mm; eluent:CO₂ + 25% EtOH + 2% diethylamine; enantiomer eluting first 14.2

2.2  470 Column: CHIRALPAK ® AD-H, 5 μM (Daicel); 10 × 250 mm; eluent:CO₂ + 25% EtOH + 2% diethylamine; enantiomer eluting second 14.3

2.3  456 Column: CHIRALPAK ® AD-H, 5 μM (Daicel); 10 × 250 mm; eluent:CO₂ + 30% EtOH + 2% diethylamine; enantiomer eluting first 14.4

2.3  456 Column: CHIRALPAK ® AD-H, 5 μM (Daicel); 10 × 250 mm; eluent:CO₂ + 30% EtOH + 2% diethylamine; enantiomer eluting second 14.5

2.8  473 Column: CHIRALPAK ® IA 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 50% EtOH + 0.2% NH₄OH; enantiomer eluting first 14.6

2.8  473 Column: CHIRALPAK ® IA 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 50% EtOH + 0.2% NH₄OH; enantiomer eluting second 14.7

2.9  461 Column: CHIRALCEL ® OJ-H 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 25% MeOH + 0.2% diethylamine; enantiomer eluting first 14.8

2.9  461 Column: CHIRALCEL ® OJ-H 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 25% MeOH + 0.2% diethylamine; ; enantiomer eluting second 14.9

1.5  493 Column: CHIRALPAK ® IC 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 40% EtOH + 0.2% diethylamine; enantiomer eluting first 14.10

1.5  493 Column: CHIRALPAK ® IC 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 40% EtOH + 0.2% diethylamine; enantiomer eluting second 14.11

2.37 461 Column: CHIRALPAK ® IA 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 40% MeOH + 0.2% diethylamine; enantiomer eluting first 14.12

2.37 461 Column: CHIRALPAK ® IA 5 μM (Daicel); 250 × 4.6 mm; eluent:CO₂ + 40% MeOH + 0.2% diethylamine; enantiomer eluting second a Absolutestereochemistry at THF moiety as indicated; absolute stereochemistry atsulphoximine moiety assigned arbitrarily

The invention claimed is:
 1. A compound of formula

wherein Ar is

wherein X is CH or N; R³ is H, halogen, CN or C(═O)—NH₂; and R⁴ is

 wherein

is a single or a double bond; n is 0 or 1; Y is O or NR^(N1); R^(N1) isselected from the group consisting of H, C₁₋₃-alkyl, —C(O)—C₁₋₃-alkyl,—C(O)—O—(CH₂)₁₋₃-phenyl and SO₂—C₁₋₃-alkyl; R⁷ is selected from thegroup consisting of F, CN, OH, —O—(C₁₋₃-alkyl),—O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and—O—C(O)—C₁₋₄-alkyl; and R⁹ is H, or R⁹ together with R⁷ form —CH₂— or—(CH₂)₂—; wherein each alkyl group mentioned in the definition of R^(N1)and R⁷ is optionally substituted with one or more F or —O—(C₁₋₃-alkyl);R¹ is

 wherein R⁵ is selected from the group consisting of C₁₋₅-alkyl,C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl, heteroaryl,and aryl, wherein each alkyl group of R⁵ is optionally substituted withone or more F or with one —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl,—O-heterocyclyl, C₃₋₇-cyclo-alkyl, heterocyclyl or phenyl; and R⁶ isC₁₋₃-alkyl which is optionally substituted with one or more F, orwherein R⁵ and R⁶ together with the sulfur atom to which they areattached form a 3 to 7-membered saturated or partly unsaturatedheterocycle that further to the sulfur atom may contain one additionalheteroatom selected from the group consisting of O, S and NR^(N2),wherein R^(N2) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),—C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl), —C(═O)—NH₂,—C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl); andwherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶ together withthe sulfur atom to which they are attached may each be independentlysubstituted with halogen, CN, OH, C₁₋₃-alkyl or —O—(C₁₋₃-alkyl); and R²is selected from the group consisting of halogen, CN, OH, C₁₋₃-alkyl,C₃₋₅-cycloalkyl and —O—(C₁₋₃-alkyl), wherein each alkyl group isoptionally substituted with one or more F; and R^(x) is H or halogen;and wherein, if not otherwise specified, each alkyl group in the abovedefinitions is linear or branched and may be substituted with one tothree F; or a stereoisomer or salt thereof.
 2. A compound according toclaim 1, wherein R¹ is selected from the group consisting of:

wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl, wherein the alkylgroup is optionally substituted with one to three F or with one —O—CH₃or phenyl; and R⁶ is C₁₋₃-alkyl which is optionally substituted with oneto three F; or wherein R⁵ and R⁶ together with the sulfur atom to whichthey are attached form a 4-, 5- or 6-membered saturated heterocycle thatis optionally substituted with OH or CH₃; or a salt thereof.
 3. Acompound according to claim 1, wherein R² is selected from the groupconsisting of F, Cl, Br, CH₃, CF₃, cyclopropyl and —O—(C₁₋₂-alkyl),wherein each alkyl group is optionally substituted with one to three F;and Rx is H; or a salt thereof.
 4. A compound according to claim 1,wherein Ar is selected from the group consisting of:

wherein X is CH or N; R³ is H, F or Cl; and R⁴ is as defined in claim 1,or a salt thereof.
 5. A compound according to claim 1 wherein R⁴ isselected from the group consisting of:

wherein

is a single or a double bond; n is 0 or 1; Y is O or NR^(N1); R^(N1) isselected from the group consisting of H, C₁₋₃-alkyl, —C(O)—C₁₋₃-alkyl,—C(O)—O—(CH₂)₁₋₃-phenyl and —SO₂—C₁₋₃-alkyl; and R⁷ is selected from thegroup consisting of F, CN, OH, —O—(C₁₋₃-alkyl),—O—(CH₂)₁₋₃—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and—O—C(O)—C₁₋₄-alkyl; wherein each alkyl group mentioned in the definitionof R^(N1) and R⁷ is optionally substituted with one or more F or—O—(C₁₋₃-alkyl), or a salt thereof.
 6. A compound according to claim 1,wherein R⁴ is selected from the group consisting of:

wherein R^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,—C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)-phenyl and —SO₂—C₁₋₃-alkyl; R⁷ isselected from the group consisting of F, CN, OH, —O—(C₁₋₃-alkyl),—O—(CH₂)—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and—O—C(O)—C₁₋₄-alkyl; and R^(7a) is selected from the group consisting ofOH and —O—(C₁₋₃-alkyl), wherein each alkyl group mentioned in thedefinition of R^(N1), R⁷ and R^(7a) is optionally substituted with oneor more F or one —O—(C₁₋₃-alkyl), or a pharmaceutically acceptable saltthereof.
 7. A compound according to claim 1, wherein R¹ is selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 1, wherein Ar is

wherein X is CH or N; R³ is H, F or Cl; and R⁴ is selected from thegroup consisting of:

 wherein R^(N1) is selected from the group consisting of H, C₁₋₃-alkyl,—C(O)—C₁₋₃-alkyl, —C(O)—O—(CH₂)-phenyl and —SO₂—C₁₋₃-alkyl; R⁷ isselected from the group consisting of F, CN, OH, —O—(C₁₋₃-alkyl),—O—(CH₂)—(C₃₋₇-cycloalkyl), —O—(CH₂)₁₋₃-phenyl, —O-oxetanyl and—O—C(O)—C₁₋₄-alkyl; and R^(7a) is selected from the group consisting ofOH and —O—(C₁₋₃-alkyl), wherein each alkyl group mentioned in thedefinition of R^(N1), R⁷ and R^(7a) is optionally substituted with oneor more F or one —O—(C₁₋₃-alkyl); R¹ is

wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl, wherein the alkylgroup is optionally substituted with one to three F or with one —O—CH₃or phenyl; and R⁶ is C₁₋₃-alkyl which is optionally substituted with oneto three F; or wherein R⁵ and R⁶ together with the sulfur atom to whichthey are attached form a 4-, 5- or 6-membered saturated heterocycle thatis optionally substituted with OH or CH₃; R² is selected from the groupconsisting of F, Cl, Br, CH₃, CF₃, cyclopropyl and —O—(C₁₋₂-alkyl),wherein each alkyl group is optionally substituted with one to three F;and R^(x) is H or F; or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 1, wherein Ar is selected from the groupconsisting of:

R¹ is selected from the group consisting of:

R² is selected from the group consisting of F, Cl, CH₃ and —O—CH₃; andR^(x) is H; or a pharmaceutically acceptable salt thereof.
 10. Acompound according to claim 1 selected from:

or a the pharmaceutically acceptable salt thereof.
 11. Apharmaceutically acceptable salt of a compound according to claim
 1. 12.Pharmaceutical composition comprising a compound according to claim 1 ora pharmaceutically acceptable salt thereof and optionally apharmaceutically acceptable carrier.
 13. Pharmaceutical compositionaccording to claim 12 further comprising an additional therapeuticagent.
 14. Pharmaceutical composition according to claim 13 wherein theadditional therapeutic agent is selected from an antidiabetic agent, alipid lowering agent, a cardiovascular agent, an antihypertensive agent,a diuretic agent, a thrombocyte aggregation inhibitor, an antineoplasticagent or an anti-obesity agent.
 15. A method of treating metabolicdiseases, hematopoietic disorders, neurodegenerative diseases, kidneydamage, inflammatory disorders and cancer and their consecutivecomplications and diseases, wherein said method comprises administrationof a pharmaceutically active amount of a compound according to claim 1or a pharmaceutically acceptable salt thereof to a patient in needthereof.
 16. A method of treating diabetes, wherein said methodcomprises administration of a pharmaceutically active amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof to a patient in need thereof.
 17. The method according to claim15, wherein the method comprises concomitant or sequentialadministration to a patient in combination with an additionaltherapeutic agent.
 18. The method according to claim 16, wherein themethod comprises concomitant or sequential administration to a patientin combination with an additional therapeutic agent.
 19. A method oftreating metabolic diseases of the carbohydrate and/or lipid metabolismand their consecutive complications and disorders, wherein said methodcomprises administration of a pharmaceutically active amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof to a patient in need thereof.